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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.
Understanding how antibody to SARS-CoV-2 evolve during infection may provide important insight into therapeutic approaches to prevent fatal COVID-19 illness and vaccines. Here, we profile the antibody response of 162 well-characterized COVID-19 symptomatic patients followed longitudinally for up to eight months from symptom onset. Using two newly developed assays we detect SARS-CoV-2 neutralization and antibodies binding to Spike antigens and nucleoprotein as well as to Spike S2 antigen of seasonal beta-coronaviruses, and to hemagglutinin of the H1N1 flu virus. Presence of neutralizing antibodies withing the first weeks from symptom onset correlates with time to a negative swab result (p=0.002) while lack of neutralization with an increased risk of a fatal disease outcome (HR 2.918, 95%CI 1.321-6.449; p=0.008). Neutralizing antibody titers progressively drop after 5-8 weeks but are still detectable up to 8 months in the majority of recovered patients regardless of age or co-morbidities. IgG to Spike antigens are the best correlate of neutralization. Antibody responses to seasonal coronaviruses are temporary boosted and parallel those to SARS-CoV-2 without dampening the specific response or worsening disease progression. Thus, a compromised immune response to the Spike rather than an enhanced one is a major trait of patients with critical conditions. Patients should be promptly identified and immediately start therapeutic interventions aimed at restoring their immunity.
Stefania Dispinseri; Massimiliano Secchi; Maria Franca Pirillo; Monica Tolazzi; Martina Borghi; Cristina Brigatti; Maria Laura De Angelis; Marco Baratella; Elena Bazzigaluppi; Giulietta Venturi; Francesca Sironi; Andrea Canitano; Ilaria Marzinotto; Cristina Tresoldi; Fabio Ciceri; Lorenzo Piemonti; Donatella Negri; Andrea Cara; Vito Lampasona; Gabriella Scarlatti. COVID-BioB Cohort Study: the neutralizing antibody response to SARS-CoV-2 in symptomatic COVID-19 is persistent and critical for virus control and survival. 2021, 1 .
AMA StyleStefania Dispinseri, Massimiliano Secchi, Maria Franca Pirillo, Monica Tolazzi, Martina Borghi, Cristina Brigatti, Maria Laura De Angelis, Marco Baratella, Elena Bazzigaluppi, Giulietta Venturi, Francesca Sironi, Andrea Canitano, Ilaria Marzinotto, Cristina Tresoldi, Fabio Ciceri, Lorenzo Piemonti, Donatella Negri, Andrea Cara, Vito Lampasona, Gabriella Scarlatti. COVID-BioB Cohort Study: the neutralizing antibody response to SARS-CoV-2 in symptomatic COVID-19 is persistent and critical for virus control and survival. . 2021; ():1.
Chicago/Turabian StyleStefania Dispinseri; Massimiliano Secchi; Maria Franca Pirillo; Monica Tolazzi; Martina Borghi; Cristina Brigatti; Maria Laura De Angelis; Marco Baratella; Elena Bazzigaluppi; Giulietta Venturi; Francesca Sironi; Andrea Canitano; Ilaria Marzinotto; Cristina Tresoldi; Fabio Ciceri; Lorenzo Piemonti; Donatella Negri; Andrea Cara; Vito Lampasona; Gabriella Scarlatti. 2021. "COVID-BioB Cohort Study: the neutralizing antibody response to SARS-CoV-2 in symptomatic COVID-19 is persistent and critical for virus control and survival." , no. : 1.
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.
Colorectal cancer (CRC) is the third commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide. Global CRC burden is expected to increase by 60% in the next decade, with low-income countries experiencing an escalation of CRC incidence and mortality in parallel to the adoption of western lifestyles. CRC incidence is also sharply increasing in individuals younger than 50 years, often presenting at advanced stages and with aggressive features. Both genetic and environmental factors have been recognized as major contributors for the development of CRC, the latter including diet-related conditions such as chronic inflammation and obesity. In particular, a diet rich in fat and sugars (Western-style diet, WSD) has been shown to induce multiple pathophysiological changes in the intestine linked to an increased risk of CRC. In this scenario, dietary factors have been recently shown to play novel unexpected roles in the regulation of intestinal stem cells (ISCs) and of the gut microbiota, which represent the two main biological systems responsible for intestinal homeostasis. Furthermore, diet is increasingly recognized to play a key role in the neoplastic transformation of ISCs and in the metabolic regulation of colorectal cancer stem cells. This review illustrates novel discoveries on the role of dietary components in regulating intestinal homeostasis and colorectal tumorigenesis. Particular focus is dedicated to new areas of research with potential clinical relevance including the effect of food components on ISCs and cancer stem cells (CSCs), the existence of CRC-specific microbial signatures and the alterations of intestinal homeostasis potentially involved in early-onset CRC. New insights on the role of dietary factors in intestinal regulation will provide new tools not only for the prevention and early diagnosis of CRC but also for improving the effectiveness of current CRC therapies.
Federica Francescangeli; Maria Laura De Angelis; Ann Zeuner. Dietary Factors in the Control of Gut Homeostasis, Intestinal Stem Cells, and Colorectal Cancer. Nutrients 2019, 11, 2936 .
AMA StyleFederica Francescangeli, Maria Laura De Angelis, Ann Zeuner. Dietary Factors in the Control of Gut Homeostasis, Intestinal Stem Cells, and Colorectal Cancer. Nutrients. 2019; 11 (12):2936.
Chicago/Turabian StyleFederica Francescangeli; Maria Laura De Angelis; Ann Zeuner. 2019. "Dietary Factors in the Control of Gut Homeostasis, Intestinal Stem Cells, and Colorectal Cancer." Nutrients 11, no. 12: 2936.
Breast cancer is the most frequent cancer among women worldwide. Therapeutic strategies to prevent or treat metastatic disease are still inadequate although great progress has been made in treating early-stage breast cancer. Cancer stem-like cells (CSCs) that are endowed with high plasticity and self-renewal properties have been shown to play a key role in breast cancer development, progression, and metastasis. A subpopulation of CSCs that combines tumor-initiating capacity and a dormant/quiescent/slow cycling status is present throughout the clinical history of breast cancer patients. Dormant/quiescent/slow cycling CSCs are a key component of tumor heterogeneity and they are responsible for chemoresistance, tumor migration, and metastatic dormancy, defined as the ability of CSCs to survive in target organs and generate metastasis up to two decades after diagnosis. Understanding the strategies that are used by CSCs to resist conventional and targeted therapies, to interact with their niche, to escape immune surveillance, and finally to awaken from dormancy is of key importance to prevent and treat metastatic cancer. This review summarizes the current understanding of mechanisms involved in CSCs chemoresistance, dissemination, and metastasis in breast cancer, with a particular focus on dormant cells. Finally, we discuss how advancements in the detection, molecular understanding, and targeting of dormant CSCs will likely open new therapeutic avenues for breast cancer treatment.
Maria De Angelis; Federica Francescangeli; Ann Zeuner. Breast Cancer Stem Cells as Drivers of Tumor Chemoresistance, Dormancy and Relapse: New Challenges and Therapeutic Opportunities. Cancers 2019, 11, 1569 .
AMA StyleMaria De Angelis, Federica Francescangeli, Ann Zeuner. Breast Cancer Stem Cells as Drivers of Tumor Chemoresistance, Dormancy and Relapse: New Challenges and Therapeutic Opportunities. Cancers. 2019; 11 (10):1569.
Chicago/Turabian StyleMaria De Angelis; Federica Francescangeli; Ann Zeuner. 2019. "Breast Cancer Stem Cells as Drivers of Tumor Chemoresistance, Dormancy and Relapse: New Challenges and Therapeutic Opportunities." Cancers 11, no. 10: 1569.
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.
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.
Biobanking of molecularly characterized colorectal cancer stem cells (CSCs) generated from individual patients and growing as spheroids in defined serum-free media offer a fast, feasible, and multi-level approach for the screening of targeted therapies and drug resistance molecular studies. By combining in vitro and in vivo analyses of cetuximab efficacy with genetic data on an ongoing collection of stem cell-enriched spheroids, we describe the identification and preliminary characterization of microsatellite stable (MSS) CSCs that, despite the presence of the KRAS (G12D) mutation, display epidermal growth factor (EGF)-dependent growth and are strongly inhibited by anti-EGF-receptor (EGFR) treatment. In parallel, we detected an increased resistance to anti-EGFR therapy of microsatellite instable (MSI) CSC lines irrespective of KRAS mutational status. MSI CSC lines carried mutations in genes coding for proteins with a role in RAS and calcium signaling, highlighting the role of a genomically unstable context in determining anti-EGFR resistance. Altogether, these results argue for a multifactorial origin of anti-EGFR resistance that emerges as the effect of multiple events targeting direct and indirect regulators of the EGFR pathway. An improved understanding of key molecular determinants of sensitivity/resistance to EGFR inhibition will be instrumental to optimize the clinical efficacy of anti-EGFR agents, representing a further step towards personalized treatments.
Maria Laura De Angelis; Alessandro Bruselles; Federica Francescangeli; Flavia Pucilli; Sara Vitale; Ann Zeuner; Marco Tartaglia; Marta Baiocchi. Colorectal cancer spheroid biobanks: multi-level approaches to drug sensitivity studies. Cell Biology and Toxicology 2018, 34, 459 -469.
AMA StyleMaria Laura De Angelis, Alessandro Bruselles, Federica Francescangeli, Flavia Pucilli, Sara Vitale, Ann Zeuner, Marco Tartaglia, Marta Baiocchi. Colorectal cancer spheroid biobanks: multi-level approaches to drug sensitivity studies. Cell Biology and Toxicology. 2018; 34 (6):459-469.
Chicago/Turabian StyleMaria Laura De Angelis; Alessandro Bruselles; Federica Francescangeli; Flavia Pucilli; Sara Vitale; Ann Zeuner; Marco Tartaglia; Marta Baiocchi. 2018. "Colorectal cancer spheroid biobanks: multi-level approaches to drug sensitivity studies." Cell Biology and Toxicology 34, no. 6: 459-469.
Treatment of lung cancer is an unmet need as it accounts for the majority of cancer deaths worldwide. The development of new therapies urges the identification of potential targets. MicroRNAs' expression is often deregulated in cancer and their modulation has been proposed as a successful strategy to interfere with tumor cell growth and spread. We recently reported on an unbiased high-content approach to identify miRNAs regulating cell proliferation and tumorigenesis in non-small cell lung cancer (NSCLC). Here we studied the oncogenic role of miR-663 in NSCLC biology and analyzed the therapeutic potential of miR-663 targeting. We found that miR-663 regulates apoptosis by controlling mitochondrial outer membrane permeabilization (MOMP) through the expression of two novel direct targets PUMA/BBC3 and BTG2. Specifically, upon miR-663 knockdown the BH3-only protein PUMA/BBC3 directly activates mitochondrial depolarization and cell death, while BTG2 accumulation further enhances this effect by triggering p53 mitochondrial localization. Moreover, we show that miR-663 depletion is sufficient to elicit cell death in NSCLC cells and to impair tumor growth in vivo.
Micol E. Fiori; Lidia Villanova; Chiara Barbini; Maria Laura De Angelis; Ruggero De Maria. miR-663 sustains NSCLC by inhibiting mitochondrial outer membrane permeabilization (MOMP) through PUMA/BBC3 and BTG2. Cell Death & Disease 2018, 9, 49 .
AMA StyleMicol E. Fiori, Lidia Villanova, Chiara Barbini, Maria Laura De Angelis, Ruggero De Maria. miR-663 sustains NSCLC by inhibiting mitochondrial outer membrane permeabilization (MOMP) through PUMA/BBC3 and BTG2. Cell Death & Disease. 2018; 9 (2):49.
Chicago/Turabian StyleMicol E. Fiori; Lidia Villanova; Chiara Barbini; Maria Laura De Angelis; Ruggero De Maria. 2018. "miR-663 sustains NSCLC by inhibiting mitochondrial outer membrane permeabilization (MOMP) through PUMA/BBC3 and BTG2." Cell Death & Disease 9, no. 2: 49.
ObjectiveCancer stem cells (CSCs) are responsible for tumour formation and spreading, and their targeting is required for tumour eradication. There are limited therapeutic options for advanced colorectal cancer (CRC), particularly for tumours carrying RAS-activating mutations. The aim of this study was to identify novel CSC-targeting strategies.DesignTo discover potential therapeutics to be clinically investigated as single agent, we performed a screening with a panel of FDA-approved or investigational drugs on primary CRC cells enriched for CSCs (CRC-SCs) isolated from 27 patients. Candidate predictive biomarkers of efficacy were identified by integrating genomic, reverse-phase protein microarray (RPPA) and cytogenetic analyses, and validated by immunostainings. DNA replication stress (RS) was increased by employing DNA replication-perturbing or polyploidising agents.ResultsThe drug-library screening led to the identification of LY2606368 as a potent anti-CSC agent acting in vitro and in vivo in tumour cells from a considerable number of patients (∼36%). By inhibiting checkpoint kinase (CHK)1, LY2606368 affected DNA replication in most CRC-SCs, including RAS-mutated ones, forcing them into premature, lethal mitoses. Parallel genomic, RPPA and cytogenetic analyses indicated that CRC-SCs sensitive to LY2606368 displayed signs of ongoing RS response, including the phosphorylation of RPA32 and ataxia telangiectasia mutated serine/threonine kinase (ATM). This was associated with mutation(s) in TP53 and hyperdiploidy, and made these CRC-SCs exquisitely dependent on CHK1 function. Accordingly, experimental increase of RS sensitised resistant CRC-SCs to LY2606368.ConclusionsLY2606368 selectively eliminates replication-stressed, p53-deficient and hyperdiploid CRC-SCs independently of RAS mutational status. These results provide a strong rationale for biomarker-driven clinical trials with LY2606368 in patients with CRC.
Gwenola Manic; Michele Signore; Antonella Sistigu; Giorgio Russo; Francesca Corradi; Silvia Siteni; Martina Musella; Sara Vitale; Maria Laura De Angelis; Matteo Pallocca; Carla Azzurra Amoreo; Francesca Sperati; Simone Di Franco; Sabina Barresi; Eleonora Policicchio; Gabriele de Luca; Francesca De Nicola; Marcella Mottolese; Ann Zeuner; Maurizio Fanciulli; Giorgio Stassi; Marcello Maugeri-Saccà; Marta Baiocchi; Marco Tartaglia; Ilio Vitale; Ruggero De Maria. CHK1-targeted therapy to deplete DNA replication-stressed, p53-deficient, hyperdiploid colorectal cancer stem cells. Gut 2017, 67, 903 -917.
AMA StyleGwenola Manic, Michele Signore, Antonella Sistigu, Giorgio Russo, Francesca Corradi, Silvia Siteni, Martina Musella, Sara Vitale, Maria Laura De Angelis, Matteo Pallocca, Carla Azzurra Amoreo, Francesca Sperati, Simone Di Franco, Sabina Barresi, Eleonora Policicchio, Gabriele de Luca, Francesca De Nicola, Marcella Mottolese, Ann Zeuner, Maurizio Fanciulli, Giorgio Stassi, Marcello Maugeri-Saccà, Marta Baiocchi, Marco Tartaglia, Ilio Vitale, Ruggero De Maria. CHK1-targeted therapy to deplete DNA replication-stressed, p53-deficient, hyperdiploid colorectal cancer stem cells. Gut. 2017; 67 (5):903-917.
Chicago/Turabian StyleGwenola Manic; Michele Signore; Antonella Sistigu; Giorgio Russo; Francesca Corradi; Silvia Siteni; Martina Musella; Sara Vitale; Maria Laura De Angelis; Matteo Pallocca; Carla Azzurra Amoreo; Francesca Sperati; Simone Di Franco; Sabina Barresi; Eleonora Policicchio; Gabriele de Luca; Francesca De Nicola; Marcella Mottolese; Ann Zeuner; Maurizio Fanciulli; Giorgio Stassi; Marcello Maugeri-Saccà; Marta Baiocchi; Marco Tartaglia; Ilio Vitale; Ruggero De Maria. 2017. "CHK1-targeted therapy to deplete DNA replication-stressed, p53-deficient, hyperdiploid colorectal cancer stem cells." Gut 67, no. 5: 903-917.
Colorectal cancer (CRC) therapy mainly relies on the use of conventional chemotherapeutic drugs combined, in a subset of patients, with epidermal growth factor receptor [EGFR]‐targeting agents. Although CRC is considered a prototype of a cancer stem cell (CSC)‐driven tumor, the effects of both conventional and targeted therapies on the CSC compartment are largely unknown. We have optimized a protocol for colorectal CSC isolation that allowed us to obtain CSC‐enriched cultures from primary tumor specimens, with high efficiency. CSC isolation was followed by in vitro and in vivo validation, genetic characterization, and drug sensitivity analysis, thus generating panels of CSC lines with defined patterns of genetic mutations and therapy sensitivity. Colorectal CSC lines were polyclonal and maintained intratumor heterogeneity in terms of somatically acquired mutations and differentiation state. Such CSC‐enriched cultures were used to investigate the effects of both conventional and targeted therapies on the CSC compartment in vivo and to generate a proteomic picture of signaling pathways implicated in sensitivity/resistance to anti‐EGFR agents. We propose CSC lines as a sound preclinical framework to test the effects of therapies in vitro and in vivo and to identify novel determinants of therapy resistance. Significance Colorectal cancer stem cells (CSCs) have been shown to be responsible for tumor propagation, metastatic dissemination, and relapse. However, molecular pathways present in CSCs, as well as mechanisms of therapy resistance, are mostly unknown. Taking advantage of genetically characterized CSC lines derived from colorectal tumors, this study provides an extensive analysis of CSC response to EGFR‐targeted therapy in vivo and an overview of factors implicated in therapy response or resistance. Furthermore, the implementation of a biobank of molecularly annotated CSC lines provides an innovative resource for future investigations in colorectal cancer.
Maria Laura De Angelis; Ann Zeuner; Eleonora Policicchio; Giorgio Russo; Alessandro Bruselles; Michele Signore; Sara Vitale; Gabriele de Luca; Emanuela Pilozzi; Alessandra Boe; Giorgio Stassi; Lucia Ricci Vitiani; Carla Azzurra Amoreo; Alfredo Pagliuca; Federica Francescangeli; Marco Tartaglia; Ruggero De Maria; Marta Baiocchi. Cancer Stem Cell-Based Models of Colorectal Cancer Reveal Molecular Determinants of Therapy Resistance. STEM CELLS Translational Medicine 2016, 5, 511 -523.
AMA StyleMaria Laura De Angelis, Ann Zeuner, Eleonora Policicchio, Giorgio Russo, Alessandro Bruselles, Michele Signore, Sara Vitale, Gabriele de Luca, Emanuela Pilozzi, Alessandra Boe, Giorgio Stassi, Lucia Ricci Vitiani, Carla Azzurra Amoreo, Alfredo Pagliuca, Federica Francescangeli, Marco Tartaglia, Ruggero De Maria, Marta Baiocchi. Cancer Stem Cell-Based Models of Colorectal Cancer Reveal Molecular Determinants of Therapy Resistance. STEM CELLS Translational Medicine. 2016; 5 (4):511-523.
Chicago/Turabian StyleMaria Laura De Angelis; Ann Zeuner; Eleonora Policicchio; Giorgio Russo; Alessandro Bruselles; Michele Signore; Sara Vitale; Gabriele de Luca; Emanuela Pilozzi; Alessandra Boe; Giorgio Stassi; Lucia Ricci Vitiani; Carla Azzurra Amoreo; Alfredo Pagliuca; Federica Francescangeli; Marco Tartaglia; Ruggero De Maria; Marta Baiocchi. 2016. "Cancer Stem Cell-Based Models of Colorectal Cancer Reveal Molecular Determinants of Therapy Resistance." STEM CELLS Translational Medicine 5, no. 4: 511-523.
Stemness was recently depicted as a dynamic condition in normal and tumor cells. We found that the embryonic protein Cripto-1 (CR1) was expressed by normal stem cells at the bottom of colonic crypts and by cancer stem cells (CSCs) in colorectal tumor tissues. CR1-positive populations isolated from patient-derived tumor spheroids exhibited increased clonogenic capacity and expression of stem-cell-related genes. CR1 expression in tumor spheroids was variable over time, being subject to a complex regulation of the intracellular, surface and secreted protein, which was related to changes of the clonogenic capacity at the population level. CR1 silencing induced CSC growth arrest in vitro with a concomitant decrease of Src/Akt signaling, while in vivo it inhibited the growth of CSC-derived tumor xenografts and reduced CSC numbers. Importantly, CR1 silencing in established xenografts through an inducible expression system decreased CSC growth in both primary and metastatic tumors, indicating an essential role of CR1 in the regulation the CSC compartment. These results point to CR1 as a novel and dynamically regulated effector of stem cell functions in colorectal cancer.
F Francescangeli; P Contavalli; M L De Angelis; M Baiocchi; G Gambara; A Pagliuca; A Fiorenzano; C Prezioso; A Boe; M Todaro; G Stassi; N P Castro; K Watanabe; D S Salomon; R De Maria; G Minchiotti; Ann Zeuner. Dynamic regulation of the cancer stem cell compartment by Cripto-1 in colorectal cancer. Cell Death & Differentiation 2015, 22, 1700 -13.
AMA StyleF Francescangeli, P Contavalli, M L De Angelis, M Baiocchi, G Gambara, A Pagliuca, A Fiorenzano, C Prezioso, A Boe, M Todaro, G Stassi, N P Castro, K Watanabe, D S Salomon, R De Maria, G Minchiotti, Ann Zeuner. Dynamic regulation of the cancer stem cell compartment by Cripto-1 in colorectal cancer. Cell Death & Differentiation. 2015; 22 (10):1700-13.
Chicago/Turabian StyleF Francescangeli; P Contavalli; M L De Angelis; M Baiocchi; G Gambara; A Pagliuca; A Fiorenzano; C Prezioso; A Boe; M Todaro; G Stassi; N P Castro; K Watanabe; D S Salomon; R De Maria; G Minchiotti; Ann Zeuner. 2015. "Dynamic regulation of the cancer stem cell compartment by Cripto-1 in colorectal cancer." Cell Death & Differentiation 22, no. 10: 1700-13.
Cell death and differentiation is a monthly research journal focused on the exciting field of programmed cell death and apoptosis. It provides a single accessible source of information for both scientists and clinicians, keeping them up-to-date with advances in the field. It encompasses programmed cell death, cell death induced by toxic agents, differentiation and the interrelation of these with cell proliferation.
Ann Zeuner; Federica Francescangeli; Paola Contavalli; Giuseppina Zapparelli; Tiziana Apuzzo; Adriana Eramo; Marta Baiocchi; Maria Laura De Angelis; Mauro Biffoni; Giovanni Sette; Matilde Todaro; Giorgio Stassi; Ruggero De Maria. Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer. Cell Death & Differentiation 2014, 21, 1877 -1888.
AMA StyleAnn Zeuner, Federica Francescangeli, Paola Contavalli, Giuseppina Zapparelli, Tiziana Apuzzo, Adriana Eramo, Marta Baiocchi, Maria Laura De Angelis, Mauro Biffoni, Giovanni Sette, Matilde Todaro, Giorgio Stassi, Ruggero De Maria. Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer. Cell Death & Differentiation. 2014; 21 (12):1877-1888.
Chicago/Turabian StyleAnn Zeuner; Federica Francescangeli; Paola Contavalli; Giuseppina Zapparelli; Tiziana Apuzzo; Adriana Eramo; Marta Baiocchi; Maria Laura De Angelis; Mauro Biffoni; Giovanni Sette; Matilde Todaro; Giorgio Stassi; Ruggero De Maria. 2014. "Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer." Cell Death & Differentiation 21, no. 12: 1877-1888.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to exhibit therapeutic activity in cancer. However, many tumors remain resistant to treatment with TRAIL. Therefore, small molecules that potentiate the cytotoxic effects of TRAIL could be used for combinatorial therapy. Here we found that the ionophore antibiotic salinomycin acts in synergism with TRAIL, enhancing TRAIL-induced apoptosis in glioma cells. Treatment with low doses of salinomycin in combination with TRAIL augmented the activation of caspase-3 and increased TRAIL-R2 cell surface expression. TRAIL-R2 upmodulation was required for mediating the stimulatory effect of salinomycin on TRAIL-mediated apoptosis, since it was abrogated by siRNA-mediated TRAIL-R2 knockdown. Salinomycin in synergism with TRAIL exerts a marked anti-tumor effect in nude mice xenografted with human glioblastoma cells. Our results suggest that the combination of TRAIL and salinomycin may be a useful tool to overcome TRAIL resistance in glioma cells and may represent a potential drug for treatment of these tumors. Importantly, salinomycin+TRAIL were able to induce cell death of well-defined glioblastoma stem-like lines.
Alessia Calzolari; Ernestina Saulle; Maria Laura De Angelis; Luca Pasquini; Alessandra Boe; Federica Pelacchi; Lucia Ricci Vitiani; Marta Baiocchi; Ugo Testa. Salinomycin Potentiates the Cytotoxic Effects of TRAIL on Glioblastoma Cell Lines. PLOS ONE 2014, 9, e94438 .
AMA StyleAlessia Calzolari, Ernestina Saulle, Maria Laura De Angelis, Luca Pasquini, Alessandra Boe, Federica Pelacchi, Lucia Ricci Vitiani, Marta Baiocchi, Ugo Testa. Salinomycin Potentiates the Cytotoxic Effects of TRAIL on Glioblastoma Cell Lines. PLOS ONE. 2014; 9 (4):e94438.
Chicago/Turabian StyleAlessia Calzolari; Ernestina Saulle; Maria Laura De Angelis; Luca Pasquini; Alessandra Boe; Federica Pelacchi; Lucia Ricci Vitiani; Marta Baiocchi; Ugo Testa. 2014. "Salinomycin Potentiates the Cytotoxic Effects of TRAIL on Glioblastoma Cell Lines." PLOS ONE 9, no. 4: e94438.