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Colorectal cancer (CRC) mortality is mainly caused by patient refractoriness to common anti-cancer therapies and consequent metastasis formation. Besides, the notorious toxic side effects of chemotherapy are a concurrent obstacle to be tackled. Thus, new treatment approaches are needed to effectively improve patient outcomes. Compelling evidence demonstrated that cancer stem cells (CSCs) are responsible for treatment failure and relapse. New natural treatment approaches showed capabilities to selectively target the CSC subpopulation by rendering them targetable by standard cytotoxic compounds. Herein we show the anti-cancer properties of the polymethoxyflavones and prenylflavonoids extracted from Citrus sinensis and Humulus lupulus, respectively. The natural biofunctional fractions, singularly and in combination, reduced the cell viability of CRC stem cells (CR-CSCs) and synergized with 5-fluorouracil and oxaliplatin (FOX) chemotherapy. These phenomena were accompanied by a reduced S and G2/M phase of the cell cycle and upregulation of cell death-related genes. Notably, both phytoextracts in combination with FOX thwarted stemness features in CR-CSCs as demonstrated by the impaired clonogenic potential and decreased Wnt pathway activation. Extracts lowered the expression of CD44v6 and affected the expansion of metastatic CR-CSCs in patients refractory to chemotherapy. Together, this study highlights the importance of polymethoxyflavones and prenylflavonoids as natural remedies to aid oncological therapies.
Alice Turdo; Antonino Glaviano; Giacomo Pepe; Federica Calapà; Stefania Raimondo; Micol Fiori; Daniela Carbone; Manuela Basilicata; Veronica Di Sarno; Carmine Ostacolo; Barbara Parrino; Stella Cascioferro; Camilla Pecoraro; Simone Di Franco; Diana Bellavia; Miriam Gaggianesi; Veronica Veschi; Melania Lo Iacono; Gloria Ganduscio; Vincenzo Pantina; Laura Mangiapane; Maria Bongiorno; Riccardo Alessandro; Matilde Todaro; Ruggero De Maria; Patrizia Diana; Pietro Campiglia; Giorgio Stassi. Nobiletin and Xanthohumol Sensitize Colorectal Cancer Stem Cells to Standard Chemotherapy. Cancers 2021, 13, 3927 .
AMA StyleAlice Turdo, Antonino Glaviano, Giacomo Pepe, Federica Calapà, Stefania Raimondo, Micol Fiori, Daniela Carbone, Manuela Basilicata, Veronica Di Sarno, Carmine Ostacolo, Barbara Parrino, Stella Cascioferro, Camilla Pecoraro, Simone Di Franco, Diana Bellavia, Miriam Gaggianesi, Veronica Veschi, Melania Lo Iacono, Gloria Ganduscio, Vincenzo Pantina, Laura Mangiapane, Maria Bongiorno, Riccardo Alessandro, Matilde Todaro, Ruggero De Maria, Patrizia Diana, Pietro Campiglia, Giorgio Stassi. Nobiletin and Xanthohumol Sensitize Colorectal Cancer Stem Cells to Standard Chemotherapy. Cancers. 2021; 13 (16):3927.
Chicago/Turabian StyleAlice Turdo; Antonino Glaviano; Giacomo Pepe; Federica Calapà; Stefania Raimondo; Micol Fiori; Daniela Carbone; Manuela Basilicata; Veronica Di Sarno; Carmine Ostacolo; Barbara Parrino; Stella Cascioferro; Camilla Pecoraro; Simone Di Franco; Diana Bellavia; Miriam Gaggianesi; Veronica Veschi; Melania Lo Iacono; Gloria Ganduscio; Vincenzo Pantina; Laura Mangiapane; Maria Bongiorno; Riccardo Alessandro; Matilde Todaro; Ruggero De Maria; Patrizia Diana; Pietro Campiglia; Giorgio Stassi. 2021. "Nobiletin and Xanthohumol Sensitize Colorectal Cancer Stem Cells to Standard Chemotherapy." Cancers 13, no. 16: 3927.
Europe is experiencing a third wave of COVID-19 due to the spread of highly transmissible SARS-CoV-2 variants. A number of positive and negative factors constantly shape the rates of COVID-19 infections, hospitalization, and mortality. Among these factors, the rise in increasingly transmissible variants on one side and the effect of vaccinations on the other side create a picture deeply different from that of the first pandemic wave. Starting from the observation that in several European countries the number of COVID-19 infections in the second and third pandemic wave increased without a proportional rise in disease severity and mortality, we hypothesize the existence of an additional factor influencing SARS-CoV-2 dynamics. This factor consists of an immune defence against severe COVID-19, provided by SARS-CoV-2-specific T cells progressively developing upon natural exposure to low virus doses present in populated environments. As suggested by recent studies, low-dose viral particles entering the respiratory and intestinal tracts may be able to induce T cell memory in the absence of inflammation, potentially resulting in different degrees of immunization. In this scenario, non-pharmaceutical interventions would play a double role, one in the short term by reducing the detrimental spreading of SARS-CoV-2 particles, and one in the long term by allowing the development of a widespread (although heterogeneous and uncontrollable) form of immune protection.
Maria De Angelis; Federica Francescangeli; Rachele Rossi; Alessandro Giuliani; Ruggero De Maria; Ann Zeuner. Repeated Exposure to Subinfectious Doses of SARS-CoV-2 May Promote T Cell Immunity and Protection against Severe COVID-19. Viruses 2021, 13, 961 .
AMA StyleMaria De Angelis, Federica Francescangeli, Rachele Rossi, Alessandro Giuliani, Ruggero De Maria, Ann Zeuner. Repeated Exposure to Subinfectious Doses of SARS-CoV-2 May Promote T Cell Immunity and Protection against Severe COVID-19. Viruses. 2021; 13 (6):961.
Chicago/Turabian StyleMaria De Angelis; Federica Francescangeli; Rachele Rossi; Alessandro Giuliani; Ruggero De Maria; Ann Zeuner. 2021. "Repeated Exposure to Subinfectious Doses of SARS-CoV-2 May Promote T Cell Immunity and Protection against Severe COVID-19." Viruses 13, no. 6: 961.
Cancer stem cells (CSCs) are immature, immortal cells within tumors, adept at resisting therapeutic pressure and responsible for local and distant disease recurrence. Non-genetic mechanisms of acquired resistance are increasingly being described, however molecular insights into this evolutionary process still lack. Here, we showed that Type I interferons (IFNs-I) act as molecular hubs of resistance during immunogenic chemotherapy, as they trigger the epigenetic regulator KDM1B, responsible for an adaptive, yet reversible, transcriptional rewiring of cancer cells towards stemness and immune escape. Accordingly, KDM1B pharmacological inhibition antagonizes the appearance of IFN-I-adapted CSCs, both in vitro and in vivo. Notably, IFN-I-adapted CSCs are heterogeneous in terms of multidrug resistance, plasticity, invasiveness and immunogenicity. Moreover, in breast cancer patients receiving anthracycline-based chemotherapy, IFN-I and KDM1B signatures positively correlate with CSC and immune evasion markers. Our study identifies IFN-I→KDM1B axis as a potent engine of cancer cell reprogramming and recommends KDM1B targeting an attractive adjunctive to immunogenic drugs to prevent CSC expansion and increase the long-term benefit of therapy.
Antonella Sistigu; Martina Musella; Claudia Galassi; Andrea Guarracino; Gwenola Manic; Nicoletta Manduca; Marco Pietrosanto; Manuela Helmer-Citterich; Matteo Pallocca; Maurizio Fanciulli; Anna Di Benedetto; Cristiana Ercolani; Edoardo Pescarmona; Laura Pizzuti; Francesca Sperati; Michele Signore; Sara Vitale; Giovanna Schiavoni; Fabrizio Mattei; Adele De Ninno; Luca Businaro; Valeria Lucarini; Laura Bracci; Eleonora Aricò; Giovanna Ziccheddu; Francesco Facchiano; Stefania Rossi; Massimo Sanchez; Alessandra Boe; Mauro Biffoni; Ruggero De Maria; Ilio Vitale. Type I IFNs promote cancer cell stemness by triggering the epigenetic regulator KDM1B. 2021, 1 .
AMA StyleAntonella Sistigu, Martina Musella, Claudia Galassi, Andrea Guarracino, Gwenola Manic, Nicoletta Manduca, Marco Pietrosanto, Manuela Helmer-Citterich, Matteo Pallocca, Maurizio Fanciulli, Anna Di Benedetto, Cristiana Ercolani, Edoardo Pescarmona, Laura Pizzuti, Francesca Sperati, Michele Signore, Sara Vitale, Giovanna Schiavoni, Fabrizio Mattei, Adele De Ninno, Luca Businaro, Valeria Lucarini, Laura Bracci, Eleonora Aricò, Giovanna Ziccheddu, Francesco Facchiano, Stefania Rossi, Massimo Sanchez, Alessandra Boe, Mauro Biffoni, Ruggero De Maria, Ilio Vitale. Type I IFNs promote cancer cell stemness by triggering the epigenetic regulator KDM1B. . 2021; ():1.
Chicago/Turabian StyleAntonella Sistigu; Martina Musella; Claudia Galassi; Andrea Guarracino; Gwenola Manic; Nicoletta Manduca; Marco Pietrosanto; Manuela Helmer-Citterich; Matteo Pallocca; Maurizio Fanciulli; Anna Di Benedetto; Cristiana Ercolani; Edoardo Pescarmona; Laura Pizzuti; Francesca Sperati; Michele Signore; Sara Vitale; Giovanna Schiavoni; Fabrizio Mattei; Adele De Ninno; Luca Businaro; Valeria Lucarini; Laura Bracci; Eleonora Aricò; Giovanna Ziccheddu; Francesco Facchiano; Stefania Rossi; Massimo Sanchez; Alessandra Boe; Mauro Biffoni; Ruggero De Maria; Ilio Vitale. 2021. "Type I IFNs promote cancer cell stemness by triggering the epigenetic regulator KDM1B." , no. : 1.
Cancer stem cells (CSCs) drive not only tumor initiation and expansion, but also therapeutic resistance and tumor relapse. Therefore, CSC eradication is required for effective cancer therapy. In preclinical models, CSCs demonstrated high capability to tolerate even extensive genotoxic stress, including replication stress, because they are endowed with a very robust DNA damage response (DDR). This favors the survival of DNA-damaged CSCs instead of their inhibition via apoptosis or senescence. The DDR represents a unique CSC vulnerability, but the abrogation of the DDR through the inhibition of the ATR-CHK1 axis is effective only against some subtypes of CSCs, and resistance often emerges. Here, we analyzed the impact of druggable DDR players in the response of patient-derived colorectal CSCs (CRC-SCs) to CHK1/2 inhibitor prexasertib, identifying RAD51 and MRE11 as sensitizing targets enhancing prexasertib efficacy. We showed that combined inhibition of RAD51 and CHK1 (via B02+prexasertib) or MRE11 and CHK1 (via mirin+prexasertib) kills CSCs by affecting multiple genoprotective processes. In more detail, these two prexasertib-based regimens promote CSC eradication through a sequential mechanism involving the induction of elevated replication stress in a context in which cell cycle checkpoints usually activated during the replication stress response are abrogated. This leads to uncontrolled proliferation and premature entry into mitosis of replication-stressed cells, followed by the induction of mitotic catastrophe. CRC-SCs subjected to RAD51+CHK1 inhibitors or MRE11+CHK1 inhibitors are eventually eliminated, and CRC-SC tumorspheres inhibited or disaggregated, via a caspase-dependent apoptosis. These results support further clinical development of these prexasertib-based regimens in colorectal cancer patients.
Luca Mattiello; Sara Soliman Abdel Rehim; Martina Musella; Antonella Sistigu; Andrea Guarracino; Sara Vitale; Francesca Corradi; Claudia Galassi; Francesca Sperati; Gwenola Manic; Ruggero De Maria; Ilio Vitale. The Targeting of MRE11 or RAD51 Sensitizes Colorectal Cancer Stem Cells to CHK1 Inhibition. Cancers 2021, 13, 1957 .
AMA StyleLuca Mattiello, Sara Soliman Abdel Rehim, Martina Musella, Antonella Sistigu, Andrea Guarracino, Sara Vitale, Francesca Corradi, Claudia Galassi, Francesca Sperati, Gwenola Manic, Ruggero De Maria, Ilio Vitale. The Targeting of MRE11 or RAD51 Sensitizes Colorectal Cancer Stem Cells to CHK1 Inhibition. Cancers. 2021; 13 (8):1957.
Chicago/Turabian StyleLuca Mattiello; Sara Soliman Abdel Rehim; Martina Musella; Antonella Sistigu; Andrea Guarracino; Sara Vitale; Francesca Corradi; Claudia Galassi; Francesca Sperati; Gwenola Manic; Ruggero De Maria; Ilio Vitale. 2021. "The Targeting of MRE11 or RAD51 Sensitizes Colorectal Cancer Stem Cells to CHK1 Inhibition." Cancers 13, no. 8: 1957.
Cancer stem cells (CSCs) are tumor subpopulations driving disease development, progression, relapse and therapy resistance, and their targeting ensures tumor eradication. CSCs display heterogeneous replication stress (RS), but the functionality/relevance of the RS response (RSR) centered on the ATR-CHK1 axis is debated. Here, we show that the RSR is efficient in primary CSCs from colorectal cancer (CRC-SCs), and describe unique roles for PARP1 and MRE11/RAD51. First, we demonstrated that PARP1 is upregulated in CRC-SCs resistant to several replication poisons and RSR inhibitors (RSRi). In these cells, PARP1 modulates replication fork speed resulting in low constitutive RS. Second, we showed that MRE11 and RAD51 cooperate in the genoprotection and mitosis execution of PARP1-upregulated CRC-SCs. These roles represent therapeutic vulnerabilities for CSCs. Indeed, PARP1i sensitized CRC-SCs to ATRi/CHK1i, inducing replication catastrophe, and prevented the development of resistance to CHK1i. Also, MRE11i + RAD51i selectively killed PARP1-upregulated CRC-SCs via mitotic catastrophe. These results provide the rationale for biomarker-driven clinical trials in CRC using distinct RSRi combinations.
Gwenola Manic; Martina Musella; Francesca Corradi; Antonella Sistigu; Sara Vitale; Sara Soliman Abdel Rehim; Luca Mattiello; Eva Malacaria; Claudia Galassi; Michele Signore; Matteo Pallocca; Stefano Scalera; Frauke Goeman; Francesca De Nicola; Andrea Guarracino; Rosa Pennisi; Fabrizio Antonangeli; Francesca Sperati; Marta Baiocchi; Mauro Biffoni; Maurizio Fanciulli; Marcello Maugeri-Saccà; Annapaola Franchitto; Pietro Pichierri; Ruggero De Maria; Ilio Vitale. Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51. Cell Death & Differentiation 2021, 28, 1 -23.
AMA StyleGwenola Manic, Martina Musella, Francesca Corradi, Antonella Sistigu, Sara Vitale, Sara Soliman Abdel Rehim, Luca Mattiello, Eva Malacaria, Claudia Galassi, Michele Signore, Matteo Pallocca, Stefano Scalera, Frauke Goeman, Francesca De Nicola, Andrea Guarracino, Rosa Pennisi, Fabrizio Antonangeli, Francesca Sperati, Marta Baiocchi, Mauro Biffoni, Maurizio Fanciulli, Marcello Maugeri-Saccà, Annapaola Franchitto, Pietro Pichierri, Ruggero De Maria, Ilio Vitale. Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51. Cell Death & Differentiation. 2021; 28 (7):1-23.
Chicago/Turabian StyleGwenola Manic; Martina Musella; Francesca Corradi; Antonella Sistigu; Sara Vitale; Sara Soliman Abdel Rehim; Luca Mattiello; Eva Malacaria; Claudia Galassi; Michele Signore; Matteo Pallocca; Stefano Scalera; Frauke Goeman; Francesca De Nicola; Andrea Guarracino; Rosa Pennisi; Fabrizio Antonangeli; Francesca Sperati; Marta Baiocchi; Mauro Biffoni; Maurizio Fanciulli; Marcello Maugeri-Saccà; Annapaola Franchitto; Pietro Pichierri; Ruggero De Maria; Ilio Vitale. 2021. "Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51." Cell Death & Differentiation 28, no. 7: 1-23.
Background The deeper knowledge of non–small-cell lung cancer (NSCLC) biology and the discovery of driver molecular alterations have opened the era of precision medicine in lung oncology, thus significantly revolutionizing the diagnostic and therapeutic approach to NSCLC. In Italy, however, molecular assessment remains heterogeneous across the country, and numbers of patients accessing personalized treatments remain relatively low. Nationwide programs have demonstrated that the creation of consortia represent a successful strategy to increase the number of patients with a molecular classification. Patients and Methods The Alliance Against Cancer (ACC), a network of 25 Italian Research Institutes, has developed a targeted sequencing panel for the detection of genomic alterations in 182 genes in patients with a diagnosis of NSCLC (ACC lung panel). One thousand metastatic NSCLC patients will be enrolled onto a prospective trial designed to measure the sensitivity and specificity of the ACC lung panel as a tool for molecular screening compared to standard methods. Results and Conclusion The ongoing trial is part of a nationwide strategy of ACC to develop infrastructures and improve competences to make the Italian research institutes independent for genomic profiling of cancer patients.
Vanesa Gregorc; Luca Mazzarella; Chiara Lazzari; Paolo Graziano; Paolo Vigneri; Carlo Genova; Luca Toschi; Gennaro Ciliberto; Laura Bonanno; Angelo Delmonte; Gabriele Bucci; Antonio Rossi; Gianmarco Motta; Simona Coco; Arianna Marinello; Simonetta Buglioni; Maria Giulia Cangi; Concetta Di Micco; Alessandro Bandiera; Silvia Bonfiglio; Lorenza Pecciarini; Alessandro Guida; Arnaud Ceol; Gianmaria Frige’; Ruggero De Maria; Pier Giuseppe Pelicci. Prospective Validation of the Italian Alliance Against Cancer Lung Panel in Patients With Advanced Non–Small-Cell Lung Cancer. Clinical Lung Cancer 2020, 22, e637 -e641.
AMA StyleVanesa Gregorc, Luca Mazzarella, Chiara Lazzari, Paolo Graziano, Paolo Vigneri, Carlo Genova, Luca Toschi, Gennaro Ciliberto, Laura Bonanno, Angelo Delmonte, Gabriele Bucci, Antonio Rossi, Gianmarco Motta, Simona Coco, Arianna Marinello, Simonetta Buglioni, Maria Giulia Cangi, Concetta Di Micco, Alessandro Bandiera, Silvia Bonfiglio, Lorenza Pecciarini, Alessandro Guida, Arnaud Ceol, Gianmaria Frige’, Ruggero De Maria, Pier Giuseppe Pelicci. Prospective Validation of the Italian Alliance Against Cancer Lung Panel in Patients With Advanced Non–Small-Cell Lung Cancer. Clinical Lung Cancer. 2020; 22 (4):e637-e641.
Chicago/Turabian StyleVanesa Gregorc; Luca Mazzarella; Chiara Lazzari; Paolo Graziano; Paolo Vigneri; Carlo Genova; Luca Toschi; Gennaro Ciliberto; Laura Bonanno; Angelo Delmonte; Gabriele Bucci; Antonio Rossi; Gianmarco Motta; Simona Coco; Arianna Marinello; Simonetta Buglioni; Maria Giulia Cangi; Concetta Di Micco; Alessandro Bandiera; Silvia Bonfiglio; Lorenza Pecciarini; Alessandro Guida; Arnaud Ceol; Gianmaria Frige’; Ruggero De Maria; Pier Giuseppe Pelicci. 2020. "Prospective Validation of the Italian Alliance Against Cancer Lung Panel in Patients With Advanced Non–Small-Cell Lung Cancer." Clinical Lung Cancer 22, no. 4: e637-e641.
Cancer cell dormancy is a common feature of human tumors and represents a major clinical barrier to the long-term efficacy of anticancer therapies. Dormant cancer cells, either in primary tumors or disseminated in secondary organs, may reawaken and relapse into a more aggressive disease. The mechanisms underpinning dormancy entry and exit strongly resemble those governing cancer cell stemness and include intrinsic and contextual cues. Cellular and molecular components of the tumor microenvironment persistently interact with cancer cells. This dialog is highly dynamic, as it evolves over time and space, strongly cooperates with intrinsic cell nets, and governs cancer cell features (like quiescence and stemness) and fate (survival and outgrowth). Therefore, there is a need for deeper insight into the biology of dormant cancer (stem) cells and the mechanisms regulating the equilibrium quiescence-versus-proliferation are vital in our pursuit of new therapeutic opportunities to prevent cancer from recurring. Here, we review and discuss microenvironmental regulations of cancer dormancy and its parallels with cancer stemness, and offer insights into the therapeutic strategies adopted to prevent a lethal recurrence, by either eradicating resident dormant cancer (stem) cells or maintaining them in a dormant state.
Antonella Sistigu; Martina Musella; Claudia Galassi; Ilio Vitale; Ruggero De Maria. Tuning Cancer Fate: Tumor Microenvironment's Role in Cancer Stem Cell Quiescence and Reawakening. Frontiers in Immunology 2020, 11, 2166 .
AMA StyleAntonella Sistigu, Martina Musella, Claudia Galassi, Ilio Vitale, Ruggero De Maria. Tuning Cancer Fate: Tumor Microenvironment's Role in Cancer Stem Cell Quiescence and Reawakening. Frontiers in Immunology. 2020; 11 ():2166.
Chicago/Turabian StyleAntonella Sistigu; Martina Musella; Claudia Galassi; Ilio Vitale; Ruggero De Maria. 2020. "Tuning Cancer Fate: Tumor Microenvironment's Role in Cancer Stem Cell Quiescence and Reawakening." Frontiers in Immunology 11, no. : 2166.
Intense research is being conducted using flow cytometers available in clinically oriented laboratories to assess extracellular vesicles (EVs) surface cargo in a variety of diseases. Using EVs of various sizes purified from the HT29 human colorectal adenocarcinoma cell line, we report on the difficulty to assess small and medium sized EVs by conventional flow cytometer that combines light side scatter off a 405 nm laser with the fluorescent signal from the EVs general labels Calcein-green and Calcein-violet, and surface markers. Small sized EVs (~70 nm) immunophenotyping failed, consistent with the scarcity of monoclonal antibody binding sites, and were therefore excluded from further investigation. Medium sized EVs (~250 nm) immunophenotyping was possible but their detection was plagued by an excess of coincident particles (swarm detection) and by a high abort rate; both factors affected the measured EVs concentration. By running samples containing equal amounts of Calcein-green and Calcein-violet stained medium sized EVs, we found that swarm detection produced false double positive events, a phenomenon that was significantly reduced, but not totally eliminated, by sample dilution. Moreover, running highly diluted samples required long periods of cytometer time. Present findings raise questions about the routine applicability of conventional flow cytometers for EV analysis.
Donatella Lucchetti; Alessandra Battaglia; Claudio Ricciardi-Tenore; Filomena Colella; Luigi Perelli; Ruggero De Maria; Giovanni Scambia; Alessandro Sgambato; Andrea Fattorossi. Measuring Extracellular Vesicles by Conventional Flow Cytometry: Dream or Reality? International Journal of Molecular Sciences 2020, 21, 6257 .
AMA StyleDonatella Lucchetti, Alessandra Battaglia, Claudio Ricciardi-Tenore, Filomena Colella, Luigi Perelli, Ruggero De Maria, Giovanni Scambia, Alessandro Sgambato, Andrea Fattorossi. Measuring Extracellular Vesicles by Conventional Flow Cytometry: Dream or Reality? International Journal of Molecular Sciences. 2020; 21 (17):6257.
Chicago/Turabian StyleDonatella Lucchetti; Alessandra Battaglia; Claudio Ricciardi-Tenore; Filomena Colella; Luigi Perelli; Ruggero De Maria; Giovanni Scambia; Alessandro Sgambato; Andrea Fattorossi. 2020. "Measuring Extracellular Vesicles by Conventional Flow Cytometry: Dream or Reality?" International Journal of Molecular Sciences 21, no. 17: 6257.
MicroRNAs are tiny but powerful regulators of gene expression at the post-transcriptional level. Aberrant expression of oncogenic and tumor-suppressor microRNAs has been recognized as a common feature of human cancers. Colorectal cancer represents a major clinical challenge in the developed world and the design of innovative therapeutic approaches relies on the identification of novel biological targets. Here, we perform a functional screening in colorectal cancer cells using a library of locked nucleic acid (LNA)-modified anti-miRs in order to unveil putative oncogenic microRNAs whose inhibition yields a cytotoxic effect. We identify miR-1285-3p and further explore the effect of its targeting in both commercial cell lines and primary colorectal cancer stem cells, finding induction of cell cycle arrest and apoptosis. We show that DAPK2, a known tumor-suppressor, is a novel miR-1285 target and mediates both the anti-proliferative and the pro-apoptotic effects of miR-1285 depletion. Altogether, our findings uncover a novel oncogenic microRNA in colorectal cancer and lay the foundation for further studies aiming at the development of possible therapeutic strategies based on miR-1285 targeting.
Lidia Villanova; Chiara Barbini; Cristina Piccolo; Alessandra Boe; Ruggero De Maria; Micol Eleonora Fiori. miR-1285-3p Controls Colorectal Cancer Proliferation and Escape from Apoptosis through DAPK2. International Journal of Molecular Sciences 2020, 21, 2423 .
AMA StyleLidia Villanova, Chiara Barbini, Cristina Piccolo, Alessandra Boe, Ruggero De Maria, Micol Eleonora Fiori. miR-1285-3p Controls Colorectal Cancer Proliferation and Escape from Apoptosis through DAPK2. International Journal of Molecular Sciences. 2020; 21 (7):2423.
Chicago/Turabian StyleLidia Villanova; Chiara Barbini; Cristina Piccolo; Alessandra Boe; Ruggero De Maria; Micol Eleonora Fiori. 2020. "miR-1285-3p Controls Colorectal Cancer Proliferation and Escape from Apoptosis through DAPK2." International Journal of Molecular Sciences 21, no. 7: 2423.
Cancer cells secrete small extracellular vesicles (sEVs) that are involved in the remodeling of tumor microenvironment (TME) and can promote tumor progression. The role of sEVs and their molecular key players in colon cancer stem cells differentiation are poorly understood. This study aimed to analyze the role and content of sEVs released during the differentiation of colorectal cancer stem cells. Here we show that sEVs secretion during colon cancer stem cells differentiation is partially controlled by CD147, a well-known player involved in colon cancer tumorigenesis. CD147 + sEVs activate a signaling cascade in recipient cells inducing molecular invasive features in colon cancer cells. CD147 knockdown as well as anti-CD147 antibodies impaired sEVs release and downstream effects on recipient cells and blocking multivesicular body maturation prevented sEVs release during the differentiation. Our findings reveal a functional role of CD147 in promoting sEVs release during the differentiation of colon cancer stem cells and in triggering cellular changes in recipient cells.
Donatella Lucchetti; Filomena Colella; Luigi Perelli; Claudio Ricciardi-Tenore; Federica Calapà; Micol E. Fiori; Federica Carbone; Ruggero De Maria; Alessandro Sgambato. CD147 Promotes Cell Small Extracellular Vesicles Release during Colon Cancer Stem Cells Differentiation and Triggers Cellular Changes in Recipient Cells. Cancers 2020, 12, 260 .
AMA StyleDonatella Lucchetti, Filomena Colella, Luigi Perelli, Claudio Ricciardi-Tenore, Federica Calapà, Micol E. Fiori, Federica Carbone, Ruggero De Maria, Alessandro Sgambato. CD147 Promotes Cell Small Extracellular Vesicles Release during Colon Cancer Stem Cells Differentiation and Triggers Cellular Changes in Recipient Cells. Cancers. 2020; 12 (2):260.
Chicago/Turabian StyleDonatella Lucchetti; Filomena Colella; Luigi Perelli; Claudio Ricciardi-Tenore; Federica Calapà; Micol E. Fiori; Federica Carbone; Ruggero De Maria; Alessandro Sgambato. 2020. "CD147 Promotes Cell Small Extracellular Vesicles Release during Colon Cancer Stem Cells Differentiation and Triggers Cellular Changes in Recipient Cells." Cancers 12, no. 2: 260.
Background Quiescent/slow cycling cells have been identified in several tumors and correlated with therapy resistance. However, the features of chemoresistant populations and the molecular factors linking quiescence to chemoresistance are largely unknown. Methods A population of chemoresistant quiescent/slow cycling cells was isolated through PKH26 staining (which allows to separate cells on the basis of their proliferation rate) from colorectal cancer (CRC) xenografts and subjected to global gene expression and pathway activation analyses. Factors expressed by the quiescent/slow cycling population were analyzed through lentiviral overexpression approaches for their ability to induce a dormant chemoresistant state both in vitro and in mouse xenografts. The correlation between quiescence-associated factors, CRC consensus molecular subtype and cancer prognosis was analyzed in large patient datasets. Results Untreated colorectal tumors contain a population of quiescent/slow cycling cells with stem cell features (quiescent cancer stem cells, QCSCs) characterized by a predetermined mesenchymal-like chemoresistant phenotype. QCSCs expressed increased levels of ZEB2, a transcription factor involved in stem cell plasticity and epithelial-mesenchymal transition (EMT), and of antiapototic factors pCRAF and pASK1. ZEB2 overexpression upregulated pCRAF/pASK1 levels resulting in increased chemoresistance, enrichment of cells with stemness/EMT traits and proliferative slowdown of tumor xenografts. In parallel, chemotherapy treatment of tumor xenografts induced the prevalence of QCSCs with a stemness/EMT phenotype and activation of the ZEB2/pCRAF/pASK1 axis, resulting in a chemotherapy-unresponsive state. In CRC patients, increased ZEB2 levels correlated with worse relapse-free survival and were strongly associated to the consensus molecular subtype 4 (CMS4) characterized by dismal prognosis, decreased proliferative rates and upregulation of EMT genes. Conclusions These results show that chemotherapy-naive tumors contain a cell population characterized by a coordinated program of chemoresistance, quiescence, stemness and EMT. Such population becomes prevalent upon drug treatment and is responsible for chemotherapy resistance, thus representing a key target for more effective therapeutic approaches.
Federica Francescangeli; Paola Contavalli; Maria Laura De Angelis; Silvia Careccia; Michele Signore; Tobias Longin Haas; Federico Salaris; Marta Baiocchi; Alessandra Boe; Alessandro Giuliani; Olga Tcheremenskaia; Alfredo Pagliuca; Ombretta Guardiola; Gabriella Minchiotti; Lidia Colace; Antonio Ciardi; Vito D’Andrea; Filippo La Torre; JanPaul Medema; Ruggero De Maria; Ann Zeuner. A pre-existing population of ZEB2+ quiescent cells with stemness and mesenchymal features dictate chemoresistance in colorectal cancer. Journal of Experimental & Clinical Cancer Research 2020, 39, 1 -17.
AMA StyleFederica Francescangeli, Paola Contavalli, Maria Laura De Angelis, Silvia Careccia, Michele Signore, Tobias Longin Haas, Federico Salaris, Marta Baiocchi, Alessandra Boe, Alessandro Giuliani, Olga Tcheremenskaia, Alfredo Pagliuca, Ombretta Guardiola, Gabriella Minchiotti, Lidia Colace, Antonio Ciardi, Vito D’Andrea, Filippo La Torre, JanPaul Medema, Ruggero De Maria, Ann Zeuner. A pre-existing population of ZEB2+ quiescent cells with stemness and mesenchymal features dictate chemoresistance in colorectal cancer. Journal of Experimental & Clinical Cancer Research. 2020; 39 (1):1-17.
Chicago/Turabian StyleFederica Francescangeli; Paola Contavalli; Maria Laura De Angelis; Silvia Careccia; Michele Signore; Tobias Longin Haas; Federico Salaris; Marta Baiocchi; Alessandra Boe; Alessandro Giuliani; Olga Tcheremenskaia; Alfredo Pagliuca; Ombretta Guardiola; Gabriella Minchiotti; Lidia Colace; Antonio Ciardi; Vito D’Andrea; Filippo La Torre; JanPaul Medema; Ruggero De Maria; Ann Zeuner. 2020. "A pre-existing population of ZEB2+ quiescent cells with stemness and mesenchymal features dictate chemoresistance in colorectal cancer." Journal of Experimental & Clinical Cancer Research 39, no. 1: 1-17.
An increasing number of anticancer agents has been proposed in recent years with the attempt to overcome treatment-resistant cancer cells and particularly cancer stem cells (CSC), the major culprits for tumour resistance and recurrence. However, a huge obstacle to treatment success is the ineffective delivery of drugs within the tumour environment due to limited solubility, short circulation time or inconsistent stability of compounds that, together with concomitant dose-limiting systemic toxicity, contribute to hamper the achievement of therapeutic drug concentrations. The synthetic retinoid Fenretinide (4-hydroxy (phenyl)retinamide; 4-HPR) formerly emerged as a promising anticancer agent based on pre-clinical and clinical studies. However, a major limitation of fenretinide is traditionally represented by its poor aqueous solubility/bioavailability due to its hydrophobic nature, that undermined the clinical success of previous clinical trials. Here, we developed a novel nano-micellar fenretinide formulation called bionanofenretinide (Bio-nFeR), based on drug encapsulation in an ion-pair stabilized lipid matrix, with the aim to raise fenretinide bioavailability and antitumour efficacy. Bio-nFeR displayed marked antitumour activity against lung, colon and melanoma CSC both in vitro and in tumour xenografts, in absence of mice toxicity. Bio-nFeR is suitable for oral administration, reaching therapeutic concentrations within tumours and an unprecedented therapeutic activity in vivo as single agent. Altogether, our results indicate Bio-nFeR as a novel anticancer agent with low toxicity and high activity against tumourigenic cells, potentially useful for the treatment of solid tumours of multiple origin.
Isabella Orienti; Valentina Salvati; Giovanni Sette; Massimo Zucchetti; Lucilla Bongiorno-Borbone; Angelo Peschiaroli; Lello Zolla; Federica Francescangeli; Mariella Ferrari; Cristina Matteo; Ezia Bello; Antonio Di Virgilio; Mario Falchi; Maria Laura De Angelis; Marta Baiocchi; Gerry Melino; Ruggero De Maria; Ann Zeuner; Adriana Eramo. A novel oral micellar fenretinide formulation with enhanced bioavailability and antitumour activity against multiple tumours from cancer stem cells. Journal of Experimental & Clinical Cancer Research 2019, 38, 1 -17.
AMA StyleIsabella Orienti, Valentina Salvati, Giovanni Sette, Massimo Zucchetti, Lucilla Bongiorno-Borbone, Angelo Peschiaroli, Lello Zolla, Federica Francescangeli, Mariella Ferrari, Cristina Matteo, Ezia Bello, Antonio Di Virgilio, Mario Falchi, Maria Laura De Angelis, Marta Baiocchi, Gerry Melino, Ruggero De Maria, Ann Zeuner, Adriana Eramo. A novel oral micellar fenretinide formulation with enhanced bioavailability and antitumour activity against multiple tumours from cancer stem cells. Journal of Experimental & Clinical Cancer Research. 2019; 38 (1):1-17.
Chicago/Turabian StyleIsabella Orienti; Valentina Salvati; Giovanni Sette; Massimo Zucchetti; Lucilla Bongiorno-Borbone; Angelo Peschiaroli; Lello Zolla; Federica Francescangeli; Mariella Ferrari; Cristina Matteo; Ezia Bello; Antonio Di Virgilio; Mario Falchi; Maria Laura De Angelis; Marta Baiocchi; Gerry Melino; Ruggero De Maria; Ann Zeuner; Adriana Eramo. 2019. "A novel oral micellar fenretinide formulation with enhanced bioavailability and antitumour activity against multiple tumours from cancer stem cells." Journal of Experimental & Clinical Cancer Research 38, no. 1: 1-17.
PTEN is one of the most frequently inactivated tumor suppressor genes in cancer. Loss or variation in PTEN gene/protein levels is commonly observed in a broad spectrum of human cancers, while germline PTEN mutations cause inherited syndromes that lead to increased risk of tumors. PTEN restrains tumorigenesis through different mechanisms ranging from phosphatase-dependent and independent activities, subcellular localization and protein interaction, modulating a broad array of cellular functions including growth, proliferation, survival, DNA repair, and cell motility. The main target of PTEN phosphatase activity is one of the most significant cell growth and pro-survival signaling pathway in cancer: PI3K/AKT/mTOR. Several shreds of evidence shed light on the critical role of PTEN in normal and cancer stem cells (CSCs) homeostasis, with its loss fostering the CSC compartment in both solid and hematologic malignancies. CSCs are responsible for tumor propagation, metastatic spread, resistance to therapy, and relapse. Thus, understanding how alterations of PTEN levels affect CSC hallmarks could be crucial for the development of successful therapeutic approaches. Here, we discuss the most significant findings on PTEN-mediated control of CSC state. We aim to unravel the role of PTEN in the regulation of key mechanisms specific for CSCs, such as self-renewal, quiescence/cell cycle, Epithelial-to-Mesenchymal-Transition (EMT), with a particular focus on PTEN-based therapy resistance mechanisms and their exploitation for novel therapeutic approaches in cancer treatment.
Francesca Luongo; Francesca Colonna; Federica Calapà; Sara Vitale; Micol E. Fiori; Ruggero De Maria. PTEN Tumor-Suppressor: The Dam of Stemness in Cancer. Cancers 2019, 11, 1076 .
AMA StyleFrancesca Luongo, Francesca Colonna, Federica Calapà, Sara Vitale, Micol E. Fiori, Ruggero De Maria. PTEN Tumor-Suppressor: The Dam of Stemness in Cancer. Cancers. 2019; 11 (8):1076.
Chicago/Turabian StyleFrancesca Luongo; Francesca Colonna; Federica Calapà; Sara Vitale; Micol E. Fiori; Ruggero De Maria. 2019. "PTEN Tumor-Suppressor: The Dam of Stemness in Cancer." Cancers 11, no. 8: 1076.
In the last decades, the role of the microenvironment in tumor progression and therapeutic outcome has gained increasing attention. Cancer-associated fibroblasts (CAFs) have emerged as key players among stromal cells, owing to their abundance in most solid tumors and their diverse tumor-restraining/promoting roles. The interplay between tumor cells and neighboring CAFs takes place by both paracrine signals (cytokines, exosomes and metabolites) or by the multifaceted functions of the surrounding extracellular matrix. Here, we dissect the most recent identified mechanisms underlying CAF-mediated control of tumor progression and therapy resistance, which include induction of the epithelial-to-mesenchymal transition (EMT), activation of survival pathways or stemness-related programs and metabolic reprogramming in tumor cells. Importantly, the recently unveiled heterogeneity in CAFs claims tailored therapeutic efforts aimed at eradicating the specific subset facilitating tumor progression, therapy resistance and relapse. However, despite the large amount of pre-clinical data, much effort is still needed to translate CAF-directed anti-cancer strategies from the bench to the clinic.
Micol Eleonora Fiori; Simone Di Franco; Lidia Villanova; Paola Bianca; Giorgio Stassi; Ruggero De Maria. Cancer-associated fibroblasts as abettors of tumor progression at the crossroads of EMT and therapy resistance. Molecular Cancer 2019, 18, 1 -16.
AMA StyleMicol Eleonora Fiori, Simone Di Franco, Lidia Villanova, Paola Bianca, Giorgio Stassi, Ruggero De Maria. Cancer-associated fibroblasts as abettors of tumor progression at the crossroads of EMT and therapy resistance. Molecular Cancer. 2019; 18 (1):1-16.
Chicago/Turabian StyleMicol Eleonora Fiori; Simone Di Franco; Lidia Villanova; Paola Bianca; Giorgio Stassi; Ruggero De Maria. 2019. "Cancer-associated fibroblasts as abettors of tumor progression at the crossroads of EMT and therapy resistance." Molecular Cancer 18, no. 1: 1-16.
Zika virus (ZIKV) is a flavivirus with a marked effect on fetal nervous system development. ZIKV treatment has recently been found to also have a benefit against glioblastoma, a highly aggressive brain tumor with a poor prognosis. The reported data do not completely explain the mechanism beyond this effect. Nevertheless, in the majority of the cases no adverse effect has been found in healthy adult humans. In this study, we characterized the ZIKV infection mechanism on glioblastoma stem cells, which are considered responsible for the tumor progression and resistance to conventional therapies. Moreover, we explain why the action of this virus is directed to the stem cells in the nervous system counterpart. Our results confirm the effectiveness of ZIKV treatment against glioblastoma, indicating novel molecular targets that can be introduced for more powerful therapies.
Gioacchin Iannolo; Maria Rita Sciuto; Nicola Cuscino; Roberto Pallini; Bruno Douradinha; Lucia Ricci Vitiani; Ruggero De Maria; Pier Giulio Conaldi. Zika virus infection induces MiR34c expression in glioblastoma stem cells: new perspectives for brain tumor treatments. Cell Death & Disease 2019, 10, 1 -10.
AMA StyleGioacchin Iannolo, Maria Rita Sciuto, Nicola Cuscino, Roberto Pallini, Bruno Douradinha, Lucia Ricci Vitiani, Ruggero De Maria, Pier Giulio Conaldi. Zika virus infection induces MiR34c expression in glioblastoma stem cells: new perspectives for brain tumor treatments. Cell Death & Disease. 2019; 10 (4):1-10.
Chicago/Turabian StyleGioacchin Iannolo; Maria Rita Sciuto; Nicola Cuscino; Roberto Pallini; Bruno Douradinha; Lucia Ricci Vitiani; Ruggero De Maria; Pier Giulio Conaldi. 2019. "Zika virus infection induces MiR34c expression in glioblastoma stem cells: new perspectives for brain tumor treatments." Cell Death & Disease 10, no. 4: 1-10.
The pressure towards innovation and creation of new model systems in regenerative medicine and cancer research has fostered the development of novel potential therapeutic applications. Kidney injuries provoke a high request of organ transplants making it the most demanding system in the field of regenerative medicine. Furthermore, renal cancer frequently threaten patients’ life and aggressive forms still remain difficult to treat. Ethical issues related to the use of embryonic stem cells, has fueled research on adult, patient-specific pluripotent stem cells as a model for discovery and therapeutic development, but to date, normal and cancerous renal experimental models are lacking. Several research groups are focusing on the development of organoid cultures. Since organoids mimic the original tissue architecture in vitro, they represent an excellent model for tissue engineering studies and cancer therapy testing. We established normal and tumor renal cell carcinoma organoids previously maintained in a heterogeneous multi-clone stem cell-like enriching medium. Starting from adult normal kidney specimens, we were able to isolate and propagate organoid 3D-structures composed of both differentiated and undifferentiated cells while expressing nephron specific markers. Furthermore, we were capable to establish organoids derived from cancer tissues although with a success rate inferior to that of their normal counterpart. Cancer cultures displayed epithelial and mesenchymal phenotype while retaining tumor specific markers. Of note, tumor organoids recapitulated neoplastic masses when orthotopically injected into immunocompromised mice. Our data suggest an innovative approach of long-term establishment of normal- and cancer-derived renal organoids obtained from cultures of fleshly dissociated adult tissues. Our results pave the way to organ replacement pioneering strategies as well as to new models for studying drug-induced nephrotoxicity and renal diseases. Along similar lines, deriving organoids from renal cancer patients opens unprecedented opportunities for generation of preclinical models aimed at improving therapeutic treatments.
Ludovica Grassi; Romina Alfonsi; Federica Francescangeli; Michele Signore; Maria Laura De Angelis; Antonio Addario; Manuela Costantini; Elisabetta Flex; Andrea Ciolfi; Simone Pizzi; Alessandro Bruselles; Matteo Pallocca; Giuseppe Simone; Mustapha Haoui; Mario Falchi; Michele Milella; Steno Sentinelli; Paola Di Matteo; Emilia Stellacci; Michele Gallucci; Giovanni Muto; Marco Tartaglia; Ruggero De Maria; Désirée Bonci. Organoids as a new model for improving regenerative medicine and cancer personalized therapy in renal diseases. Cell Death & Disease 2019, 10, 1 -15.
AMA StyleLudovica Grassi, Romina Alfonsi, Federica Francescangeli, Michele Signore, Maria Laura De Angelis, Antonio Addario, Manuela Costantini, Elisabetta Flex, Andrea Ciolfi, Simone Pizzi, Alessandro Bruselles, Matteo Pallocca, Giuseppe Simone, Mustapha Haoui, Mario Falchi, Michele Milella, Steno Sentinelli, Paola Di Matteo, Emilia Stellacci, Michele Gallucci, Giovanni Muto, Marco Tartaglia, Ruggero De Maria, Désirée Bonci. Organoids as a new model for improving regenerative medicine and cancer personalized therapy in renal diseases. Cell Death & Disease. 2019; 10 (3):1-15.
Chicago/Turabian StyleLudovica Grassi; Romina Alfonsi; Federica Francescangeli; Michele Signore; Maria Laura De Angelis; Antonio Addario; Manuela Costantini; Elisabetta Flex; Andrea Ciolfi; Simone Pizzi; Alessandro Bruselles; Matteo Pallocca; Giuseppe Simone; Mustapha Haoui; Mario Falchi; Michele Milella; Steno Sentinelli; Paola Di Matteo; Emilia Stellacci; Michele Gallucci; Giovanni Muto; Marco Tartaglia; Ruggero De Maria; Désirée Bonci. 2019. "Organoids as a new model for improving regenerative medicine and cancer personalized therapy in renal diseases." Cell Death & Disease 10, no. 3: 1-15.
Data from 423 human epidermal growth factor receptor 2‐negative (HER2−), hormone receptor‐positive (HR+) advanced breast cancer (aBC) patients treated with palbociclib and endocrine therapy (ET) were provided by 35 Italian cancer centers and analyzed for treatment outcomes. Overall, 158 patients were treated in first line and 265 in second/later lines. We observed 19 complete responses and 112 partial responses. The overall response rate (ORR) was 31% (95% confidence interval [CI], 26.6–35.4) and clinical benefit was 52.7% (95% CI, 48–57.5). ORR was negatively affected by prior exposure to everolimus/exemestane ( p = 0.002) and favorably influenced by early line‐treatment ( p < 0.0001). At 6 months, median progression‐free survival was 12 months (95% CI, 8–16) and median overall survival was 24 months (95% CI, 17–30). More favorable outcomes were associated with palbociclib in early lines, no visceral metastases and no prior everolimus/exemestane. The main toxicity reported was neutropenia. Our results provide further support to the use of palbociclib with ET in HER2−, HR+ aBC. Differences in outcomes across patients subsets remain largely unexplained.
Laura Pizzuti; Antonio Giordano; Andrea Michelotti; Marco Mazzotta; Clara Natoli; Teresa Gamucci; Claudia De Angelis; Elisabetta Landucci; Lucrezia Diodati; Laura Iezzi; Lucia Mentuccia; Agnese Fabbri; Maddalena Barba; Giuseppe Sanguineti; Paolo Marchetti; Silverio Tomao; Luciano Mariani; Ida Paris; Vito Lorusso; Simona Vallarelli; Alessandra Cassano; Francesca Aroldi; Armando Orlandi; Luca Moscetti; Domenico Sergi; Maria Giuseppina Sarobba; Giuseppe Tonini; Daniele Santini; Valentina Sini; Enzo Veltri; Angela Vaccaro; Laura Ferrari; Michele DE Tursi; Nicola Tinari; Antonino Grassadonia; Filippo Greco; Andrea Botticelli; Nicla La Verde; Claudio Zamagni; Daniela Rubino; Enrico Cortesi; Valentina Magri; Giulia Pomati; Simone Scagnoli; Elisabetta Capomolla; Ramy Kayal; Angelo Fedele Scinto; Domenico Corsi; Marina Cazzaniga; Lucio Laudadio; Samantha Forciniti; Maria Mancini; Luisa Carbognin; Patrizia Seminara; Sandro Barni; Riccardo Samaritani; Mario Roselli; Ilaria Portarena; Antonio Russo; Corrado Ficorella; Katia Cannita; Silvia Carpano; Mirco Pistelli; Rossana Berardi; Ruggero De Maria; Isabella Sperduti; Gennaro Ciliberto; Patrizia Vici. Palbociclib plus endocrine therapy in HER2 negative, hormonal receptor‐positive, advanced breast cancer: A real‐world experience. Journal of Cellular Physiology 2018, 234, 7708 -7717.
AMA StyleLaura Pizzuti, Antonio Giordano, Andrea Michelotti, Marco Mazzotta, Clara Natoli, Teresa Gamucci, Claudia De Angelis, Elisabetta Landucci, Lucrezia Diodati, Laura Iezzi, Lucia Mentuccia, Agnese Fabbri, Maddalena Barba, Giuseppe Sanguineti, Paolo Marchetti, Silverio Tomao, Luciano Mariani, Ida Paris, Vito Lorusso, Simona Vallarelli, Alessandra Cassano, Francesca Aroldi, Armando Orlandi, Luca Moscetti, Domenico Sergi, Maria Giuseppina Sarobba, Giuseppe Tonini, Daniele Santini, Valentina Sini, Enzo Veltri, Angela Vaccaro, Laura Ferrari, Michele DE Tursi, Nicola Tinari, Antonino Grassadonia, Filippo Greco, Andrea Botticelli, Nicla La Verde, Claudio Zamagni, Daniela Rubino, Enrico Cortesi, Valentina Magri, Giulia Pomati, Simone Scagnoli, Elisabetta Capomolla, Ramy Kayal, Angelo Fedele Scinto, Domenico Corsi, Marina Cazzaniga, Lucio Laudadio, Samantha Forciniti, Maria Mancini, Luisa Carbognin, Patrizia Seminara, Sandro Barni, Riccardo Samaritani, Mario Roselli, Ilaria Portarena, Antonio Russo, Corrado Ficorella, Katia Cannita, Silvia Carpano, Mirco Pistelli, Rossana Berardi, Ruggero De Maria, Isabella Sperduti, Gennaro Ciliberto, Patrizia Vici. Palbociclib plus endocrine therapy in HER2 negative, hormonal receptor‐positive, advanced breast cancer: A real‐world experience. Journal of Cellular Physiology. 2018; 234 (6):7708-7717.
Chicago/Turabian StyleLaura Pizzuti; Antonio Giordano; Andrea Michelotti; Marco Mazzotta; Clara Natoli; Teresa Gamucci; Claudia De Angelis; Elisabetta Landucci; Lucrezia Diodati; Laura Iezzi; Lucia Mentuccia; Agnese Fabbri; Maddalena Barba; Giuseppe Sanguineti; Paolo Marchetti; Silverio Tomao; Luciano Mariani; Ida Paris; Vito Lorusso; Simona Vallarelli; Alessandra Cassano; Francesca Aroldi; Armando Orlandi; Luca Moscetti; Domenico Sergi; Maria Giuseppina Sarobba; Giuseppe Tonini; Daniele Santini; Valentina Sini; Enzo Veltri; Angela Vaccaro; Laura Ferrari; Michele DE Tursi; Nicola Tinari; Antonino Grassadonia; Filippo Greco; Andrea Botticelli; Nicla La Verde; Claudio Zamagni; Daniela Rubino; Enrico Cortesi; Valentina Magri; Giulia Pomati; Simone Scagnoli; Elisabetta Capomolla; Ramy Kayal; Angelo Fedele Scinto; Domenico Corsi; Marina Cazzaniga; Lucio Laudadio; Samantha Forciniti; Maria Mancini; Luisa Carbognin; Patrizia Seminara; Sandro Barni; Riccardo Samaritani; Mario Roselli; Ilaria Portarena; Antonio Russo; Corrado Ficorella; Katia Cannita; Silvia Carpano; Mirco Pistelli; Rossana Berardi; Ruggero De Maria; Isabella Sperduti; Gennaro Ciliberto; Patrizia Vici. 2018. "Palbociclib plus endocrine therapy in HER2 negative, hormonal receptor‐positive, advanced breast cancer: A real‐world experience." Journal of Cellular Physiology 234, no. 6: 7708-7717.
In the past few decades, numerous approaches have been developed to investigate protein‐protein and protein‐nucleic acid interactions (PPIs and PNIs). Affinity purification methods such as co‐immunoprecipitation (co‐IP) are commonly used to detect and isolate the macromolecular complexesresulting from these interactions. In this article, we describe a two‐step co‐immunoprecipitation (TIP) technique. As compared to standard co‐IP, TIP provides increased specificity in the isolation of PPIs or PNIs under native expression conditions, dramatically reducing the abundance of nonspecific binders and thus facilitating downstream analyses of the interaction complexes. Here, we report a detailed TIP procedure that we used to purify a protein‐protein complex from Burkitt lymphoma cells and from primary human CD4+ T cells. In addition, this unit describes an application of TIP for the isolation of transcription‐factor‐bound chromatin. © 2018 by John Wiley & Sons, Inc.
Maria Rita Sciuto; Valeria Coppola; Gioacchin Iannolo; Ruggero De Maria; Tobias L. Haas. Two-Step Co-Immunoprecipitation (TIP). Current Protocols in Molecular Biology 2018, 125, e80 .
AMA StyleMaria Rita Sciuto, Valeria Coppola, Gioacchin Iannolo, Ruggero De Maria, Tobias L. Haas. Two-Step Co-Immunoprecipitation (TIP). Current Protocols in Molecular Biology. 2018; 125 (1):e80.
Chicago/Turabian StyleMaria Rita Sciuto; Valeria Coppola; Gioacchin Iannolo; Ruggero De Maria; Tobias L. Haas. 2018. "Two-Step Co-Immunoprecipitation (TIP)." Current Protocols in Molecular Biology 125, no. 1: e80.
We carried out a retrospective observational study of 264 HER2-positive advanced breast cancer (ABC) patients to explore the efficacy of first-line treatment with pertuzumab/trastuzumab/taxane in real-world setting. Survival data were analyzed by Kaplan Meier curves and log rank test. Median follow-up, length of pertuzumab/trastuzumab/taxane treatment and of pertuzumab, trastuzumab maintenance were 21, 4 and 15 months, respectively. The response rate was 77.3%, and the clinical benefit rate 93.6%. Median progression-free survival (mPFS) was 21 months, and median overall survival (mOS) was not reached. When comparing patients by trastuzumab-pretreatment, similar PFS were observed, although a longer OS was reached in trastuzumab-naïve patients (p = 0.02). Brain metastases at baseline and their development in course of therapy were associated with significantly shorter PFS (p = 0.0006) and shorter OS, although at a not fully statistically relevant extent (p = 0.06). The addition of maintenance endocrine therapy (ET) to pertuzumab/trastuzumab maintenance was associated with longer PFS (p = 0.0001), although no significant differences were detected in OS (p = 0.31). Results were confirmed by propensity score analysis (p = 0.003 and p = 0.46, respectively). In multivariate models, longer PFS was related to lower Performance Status (PS) (p = 0.07), metastatic stage at diagnosis (p = 0.006) and single metastatic site (p < 0.0001). An OS advantage was observed with lower PS (p < 0.0001), single metastatic site (p = 0.004), no prior exposure to trastuzumab (p = 0.004) and response to pertuzumab-based treatment (p = 0.003). Our results confirm that trastuzumab/pertuzumab/taxane is the standard of care as first-line treatment of patients with HER2-positive ABC even in the real-world setting. Moreover, the double-maintenance therapy (HER2 block and ET) is strongly recommended when feasible.
Teresa Gamucci; Laura Pizzuti; Clara Natoli; Lucia Mentuccia; Isabella Sperduti; Maddalena Barba; Domenico Sergi; Laura Iezzi; Marcello Maugeri-Saccà; Angela Vaccaro; Emanuela Magnolfi; Alain Gelibter; Giacomo Barchiesi; Valentina Magri; Loretta D’Onofrio; Alessandra Cassano; Ernesto Rossi; Andrea Botticelli; Luca Moscetti; Claudia Omarini; Maria Agnese Fabbri; Angelo Fedele Scinto; Domenico Corsi; Luisa Carbognin; Marco Mazzotta; Emilio Bria; Jennifer Foglietta; Riccardo Samaritani; Carlo Garufi; Luciano Mariani; Sandro Barni; Rosanna Mirabelli; Roberta Sarmiento; Vincenzo Graziano; Daniele Santini; Paolo Marchetti; Giuseppe Tonini; Luigi Di Lauro; Giuseppe Sanguineti; Giancarlo Paoletti; Silverio Tomao; Ruggero De Maria; Enzo Veltri; Ida Paris; Francesco Giotta; Agnese Latorre; Antonio Giordano; Gennaro Ciliberto; Patrizia Vici. A multicenter REtrospective observational study of first-line treatment with PERtuzumab, trastuzumab and taxanes for advanced HER2 positive breast cancer patients. RePer Study. Cancer Biology & Therapy 2018, 20, 192 -200.
AMA StyleTeresa Gamucci, Laura Pizzuti, Clara Natoli, Lucia Mentuccia, Isabella Sperduti, Maddalena Barba, Domenico Sergi, Laura Iezzi, Marcello Maugeri-Saccà, Angela Vaccaro, Emanuela Magnolfi, Alain Gelibter, Giacomo Barchiesi, Valentina Magri, Loretta D’Onofrio, Alessandra Cassano, Ernesto Rossi, Andrea Botticelli, Luca Moscetti, Claudia Omarini, Maria Agnese Fabbri, Angelo Fedele Scinto, Domenico Corsi, Luisa Carbognin, Marco Mazzotta, Emilio Bria, Jennifer Foglietta, Riccardo Samaritani, Carlo Garufi, Luciano Mariani, Sandro Barni, Rosanna Mirabelli, Roberta Sarmiento, Vincenzo Graziano, Daniele Santini, Paolo Marchetti, Giuseppe Tonini, Luigi Di Lauro, Giuseppe Sanguineti, Giancarlo Paoletti, Silverio Tomao, Ruggero De Maria, Enzo Veltri, Ida Paris, Francesco Giotta, Agnese Latorre, Antonio Giordano, Gennaro Ciliberto, Patrizia Vici. A multicenter REtrospective observational study of first-line treatment with PERtuzumab, trastuzumab and taxanes for advanced HER2 positive breast cancer patients. RePer Study. Cancer Biology & Therapy. 2018; 20 (2):192-200.
Chicago/Turabian StyleTeresa Gamucci; Laura Pizzuti; Clara Natoli; Lucia Mentuccia; Isabella Sperduti; Maddalena Barba; Domenico Sergi; Laura Iezzi; Marcello Maugeri-Saccà; Angela Vaccaro; Emanuela Magnolfi; Alain Gelibter; Giacomo Barchiesi; Valentina Magri; Loretta D’Onofrio; Alessandra Cassano; Ernesto Rossi; Andrea Botticelli; Luca Moscetti; Claudia Omarini; Maria Agnese Fabbri; Angelo Fedele Scinto; Domenico Corsi; Luisa Carbognin; Marco Mazzotta; Emilio Bria; Jennifer Foglietta; Riccardo Samaritani; Carlo Garufi; Luciano Mariani; Sandro Barni; Rosanna Mirabelli; Roberta Sarmiento; Vincenzo Graziano; Daniele Santini; Paolo Marchetti; Giuseppe Tonini; Luigi Di Lauro; Giuseppe Sanguineti; Giancarlo Paoletti; Silverio Tomao; Ruggero De Maria; Enzo Veltri; Ida Paris; Francesco Giotta; Agnese Latorre; Antonio Giordano; Gennaro Ciliberto; Patrizia Vici. 2018. "A multicenter REtrospective observational study of first-line treatment with PERtuzumab, trastuzumab and taxanes for advanced HER2 positive breast cancer patients. RePer Study." Cancer Biology & Therapy 20, no. 2: 192-200.
Clear cell RCC (ccRCC) accounts for approximately 75% of the renal cancer cases. Surgery treatment seems to be the best efficacious approach for the majority of patients. However, a consistent fraction (30%) of cases progress after surgery with curative intent. It is currently largely debated the use of adjuvant therapy for high-risk patients and the clinical and molecular parameters for stratifying beneficiary categories. In addition, the treatment of advanced forms lacks reliable driver biomarkers for the appropriated therapeutic choice. Thus, renal cancer patient management urges predictive molecular indicators and models for therapy-decision making. Here, we developed and optimized new models and tools for ameliorating renal cancer patient management. We isolated from fresh tumor specimens heterogeneous multi-clonal populations showing epithelial and mesenchymal characteristics coupled to stem cell phenotype. These cells retained long lasting-tumor-propagating capacity provided a therapy monitoring approach in vitro and in vivo while being able to form parental tumors when orthotopically injected and serially transplanted in immunocompromised murine hosts. In line with recent evidence of multiclonal cancer composition, we optimized in vitro cultures enriched of multiple tumor-propagating populations. Orthotopic xenograft masses recapitulated morphology, grading and malignancy of parental cancers. High-grade but not the low-grade neoplasias, resulted in efficient serial transplantation in mice. Engraftment capacity paralleled grading and recurrence frequency advocating for a prognostic value of our developed model system. Therefore, in search of novel molecular indicators for therapy decision-making, we used Reverse-Phase Protein Arrays (RPPA) to analyze a panel of total and phosphorylated proteins in the isolated populations. Tumor-propagating cells showed several deregulated kinase cascades associated with grading, including angiogenesis and m-TOR pathways. In the era of personalized therapy, the analysis of tumor propagating cells may help improve prediction of disease progression and therapy assignment. The possibility to test pharmacological response of ccRCC stem-like cells in vitro and in orthotopic models may help define a pharmacological profiling for future development of more effective therapies. Likewise, RPPA screening on patient-derived populations offers innovative approach for possible prediction of therapy response.
Simona di Martino; Gabriele De Luca; Ludovica Grassi; Giulia Federici; Romina Alfonsi; Michele Signore; Antonio Addario; Laura De Salvo; Federica Francescangeli; Massimo Sanchez; Valentina Tirelli; Giovanni Muto; Isabella Sperduti; Steno Sentinelli; Manuela Costantini; Luca Pasquini; Michele Milella; Mustapha Haoui; Giuseppe Simone; Michele Gallucci; Ruggero De Maria; Désirée Bonci. Renal cancer: new models and approach for personalizing therapy. Journal of Experimental & Clinical Cancer Research 2018, 37, 217 .
AMA StyleSimona di Martino, Gabriele De Luca, Ludovica Grassi, Giulia Federici, Romina Alfonsi, Michele Signore, Antonio Addario, Laura De Salvo, Federica Francescangeli, Massimo Sanchez, Valentina Tirelli, Giovanni Muto, Isabella Sperduti, Steno Sentinelli, Manuela Costantini, Luca Pasquini, Michele Milella, Mustapha Haoui, Giuseppe Simone, Michele Gallucci, Ruggero De Maria, Désirée Bonci. Renal cancer: new models and approach for personalizing therapy. Journal of Experimental & Clinical Cancer Research. 2018; 37 (1):217.
Chicago/Turabian StyleSimona di Martino; Gabriele De Luca; Ludovica Grassi; Giulia Federici; Romina Alfonsi; Michele Signore; Antonio Addario; Laura De Salvo; Federica Francescangeli; Massimo Sanchez; Valentina Tirelli; Giovanni Muto; Isabella Sperduti; Steno Sentinelli; Manuela Costantini; Luca Pasquini; Michele Milella; Mustapha Haoui; Giuseppe Simone; Michele Gallucci; Ruggero De Maria; Désirée Bonci. 2018. "Renal cancer: new models and approach for personalizing therapy." Journal of Experimental & Clinical Cancer Research 37, no. 1: 217.