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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.
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.
Molecular alterations are not randomly distributed in colorectal cancer (CRC), but rather clustered on the basis of primary tumor location underlying the importance of colorectal cancer sidedness. We aimed to investigate whether circulating tumor cells (CTC) characterization might help clarify how different the patterns of dissemination might be relative to the behavior of left- (LCC) compared to right-sided (RCC) cancers. We retrospectively analyzed patients with metastatic CRC who had undergone standard baseline CTC evaluation before starting any first-line systemic treatment. Enumeration of CTC in left- and right-sided tumors were compared. The highest prognostic impact was exerted by CTC in left-sided primary cancer patients, even though the lowest median number of cells was detected in this subgroup of patients. CTC exhibit phenotypic heterogeneity, with a predominant mesenchymal phenotype found in CTC from distal compared to proximal primary tumors. Most CTC in RCC patients exhibited an apoptotic pattern. CTC in left-sided colon cancer patients exhibit a predominant mesenchymal phenotype. This might imply a substantial difference in the biology of proximal and distal cancers, associated with different patterns of tumor cells dissemination. The poor prognosis of right-sided CRC is not determined by the hematogenous dissemination of tumor cells, which appears to be predominantly a passive shedding of non-viable cells. Conversely, the subgroup of poor-prognosis left-sided CRC is reliably identified by the presence of mesenchymal CTC.
Chiara Nicolazzo; Cristina Raimondi; Angela Gradilone; Alessandra Emiliani; Ann Zeuner; Federica Francescangeli; Francesca Belardinilli; Patrizia Seminara; Flavia Loreni; Valentina Magri; Silverio Tomao; Paola Gazzaniga. Circulating Tumor Cells in Right- and Left-Sided Colorectal Cancer. Cancers 2019, 11, 1042 .
AMA StyleChiara Nicolazzo, Cristina Raimondi, Angela Gradilone, Alessandra Emiliani, Ann Zeuner, Federica Francescangeli, Francesca Belardinilli, Patrizia Seminara, Flavia Loreni, Valentina Magri, Silverio Tomao, Paola Gazzaniga. Circulating Tumor Cells in Right- and Left-Sided Colorectal Cancer. Cancers. 2019; 11 (8):1042.
Chicago/Turabian StyleChiara Nicolazzo; Cristina Raimondi; Angela Gradilone; Alessandra Emiliani; Ann Zeuner; Federica Francescangeli; Francesca Belardinilli; Patrizia Seminara; Flavia Loreni; Valentina Magri; Silverio Tomao; Paola Gazzaniga. 2019. "Circulating Tumor Cells in Right- and Left-Sided Colorectal Cancer." Cancers 11, no. 8: 1042.
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.
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.
Background Several studies have raised the issue of the inadequacy of CellSearch® to detect the entire pool of circulating tumor cells (CTCs) from blood of cancer patients, suggesting that cells expressing low levels of epithelial cell adhesion molecule (EpCAM) are not recognized by the capture reagent. In this exploratory study, we aimed to evaluate the status of EpCAM in CTCs isolated from a group of metastatic colorectal cancer patients, in 40% of whom, CTC had been found to be undetected by the CellSearch® system. Methods CTCs were analyzed using both a microfiltration method (ScreenCell) and CellSearch® in parallel. Furthermore, since EpCAM exists in 2 different variants, we investigated the presence of both its intracellular domain (EpICD) and extracellular domain (EpEX) through immunofluorescence staining of CTCs on filters. Results Results from immunofluorescence experiments demonstrated that, overall, EpICD and/or EpEX was expressed in 176 CTCs detected by ScreenCell, while the CellSearch® system was able to capture only 10 CTCs. Conclusions This is the first demonstration that the low sensitivity of CellSearch® to detect CTCs in colorectal cancer patients is not due to the lack of EpCAM.
Chiara Nicolazzo; Cristina Raimondi; Federica Francescangeli; Simona Ceccarelli; Patrizia Trenta; Valentina Magri; Cinzia Marchese; Ann Zeuner; Angela Gradilone; Paola Gazzaniga. EpCAM-Expressing Circulating Tumor Cells in Colorectal Cancer. The International Journal of Biological Markers 2017, 32, 415 -420.
AMA StyleChiara Nicolazzo, Cristina Raimondi, Federica Francescangeli, Simona Ceccarelli, Patrizia Trenta, Valentina Magri, Cinzia Marchese, Ann Zeuner, Angela Gradilone, Paola Gazzaniga. EpCAM-Expressing Circulating Tumor Cells in Colorectal Cancer. The International Journal of Biological Markers. 2017; 32 (4):415-420.
Chicago/Turabian StyleChiara Nicolazzo; Cristina Raimondi; Federica Francescangeli; Simona Ceccarelli; Patrizia Trenta; Valentina Magri; Cinzia Marchese; Ann Zeuner; Angela Gradilone; Paola Gazzaniga. 2017. "EpCAM-Expressing Circulating Tumor Cells in Colorectal Cancer." The International Journal of Biological Markers 32, no. 4: 415-420.
Known molecular determinants of developmental plasticity are mainly transcription factors, while the extrinsic regulation of this process has been largely unexplored. Here we identify Cripto as one of the earliest epiblast markers and a key extracellular determinant of the naive and primed pluripotent states. We demonstrate that Cripto sustains mouse embryonic stem cell (ESC) self-renewal by modulating Wnt/β-catenin, whereas it maintains mouse epiblast stem cell (EpiSC) and human ESC pluripotency through Nodal/Smad2. Moreover, we provide unprecedented evidence that Cripto controls the metabolic reprogramming in ESCs to EpiSC transition. Remarkably, Cripto deficiency attenuates ESC lineage restriction in vitro and in vivo, and permits ESC transdifferentiation into trophectoderm lineage, suggesting that Cripto has earlier functions than previously recognized. All together, our studies provide novel insights into the current model of mammalian pluripotency and contribute to the understanding of the extrinsic regulation of the first cell lineage decision in the embryo.
Alessandro Fiorenzano; Emilia Pascale; Cristina D'aniello; Dario Acampora; Cecilia Bassalert; Francesco Russo; Gennaro Andolfi; Mauro Biffoni; Federica Francescangeli; Ann Zeuner; Claudia Angelini; Claire Chazaud; Eduardo Jorge Patriarca; Annalisa Fico; Gabriella Minchiotti. Cripto is essential to capture mouse epiblast stem cell and human embryonic stem cell pluripotency. Nature Communications 2016, 7, 12589 .
AMA StyleAlessandro Fiorenzano, Emilia Pascale, Cristina D'aniello, Dario Acampora, Cecilia Bassalert, Francesco Russo, Gennaro Andolfi, Mauro Biffoni, Federica Francescangeli, Ann Zeuner, Claudia Angelini, Claire Chazaud, Eduardo Jorge Patriarca, Annalisa Fico, Gabriella Minchiotti. Cripto is essential to capture mouse epiblast stem cell and human embryonic stem cell pluripotency. Nature Communications. 2016; 7 (1):12589.
Chicago/Turabian StyleAlessandro Fiorenzano; Emilia Pascale; Cristina D'aniello; Dario Acampora; Cecilia Bassalert; Francesco Russo; Gennaro Andolfi; Mauro Biffoni; Federica Francescangeli; Ann Zeuner; Claudia Angelini; Claire Chazaud; Eduardo Jorge Patriarca; Annalisa Fico; Gabriella Minchiotti. 2016. "Cripto is essential to capture mouse epiblast stem cell and human embryonic stem cell pluripotency." Nature Communications 7, no. 1: 12589.
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.
Although the development of bone metastasis is a major detrimental event in prostate cancer, the molecular mechanisms responsible for bone homing and destruction remain largely unknown. Here we show that loss of miR-15 and miR-16 in cooperation with increased miR-21 expression promote prostate cancer spreading and bone lesions. This combination of microRNA endows bone-metastatic potential to prostate cancer cells. Concomitant loss of miR-15/miR-16 and gain of miR-21 aberrantly activate TGF-β and Hedgehog signaling, that mediate local invasion, distant bone marrow colonization and osteolysis by prostate cancer cells. These findings establish a new molecular circuitry for prostate cancer metastasis that was validated in patients' cohorts. Our data indicate a network of biomarkers and druggable pathways to improve patient treatment.
Desiree Bonci; V Coppola; M Patrizii; Antonio Addario; A Cannistraci; F Francescangeli; R Pecci; Giovanni Muto; D Collura; Rossella Bedini; Ann Zeuner; Mauro Valtieri; S Sentinelli; M S Benassi; Michele Gallucci; P Carlini; S Piccolo; R De Maria. A microRNA code for prostate cancer metastasis. Oncogene 2015, 35, 1180 -1192.
AMA StyleDesiree Bonci, V Coppola, M Patrizii, Antonio Addario, A Cannistraci, F Francescangeli, R Pecci, Giovanni Muto, D Collura, Rossella Bedini, Ann Zeuner, Mauro Valtieri, S Sentinelli, M S Benassi, Michele Gallucci, P Carlini, S Piccolo, R De Maria. A microRNA code for prostate cancer metastasis. Oncogene. 2015; 35 (9):1180-1192.
Chicago/Turabian StyleDesiree Bonci; V Coppola; M Patrizii; Antonio Addario; A Cannistraci; F Francescangeli; R Pecci; Giovanni Muto; D Collura; Rossella Bedini; Ann Zeuner; Mauro Valtieri; S Sentinelli; M S Benassi; Michele Gallucci; P Carlini; S Piccolo; R De Maria. 2015. "A microRNA code for prostate cancer metastasis." Oncogene 35, no. 9: 1180-1192.
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‐initiating cells are responsible for tumor maintenance and relapse in solid and hematologic cancers. Although tumor‐initiating cells were initially believed to be mainly quiescent, rapidly proliferating tumorigenic cells were found in breast cancer. In colon cancer, the proliferative activity of the tumorigenic population has not been defined, although it represents an essential parameter for the development of more effective therapeutic strategies. Here, we show that tumorigenic colon cancer cells can be found in a rapidly proliferating state in vitro and in vivo, both in human tumors and mouse xenografts. Inhibitors of polo‐like kinase1 (Plk1), a mitotic kinase essential for cell proliferation, demonstrated maximal efficiency over other targeted compounds and chemotherapeutic agents in inducing death of colon cancer‐initiating cells in vitro. In vivo, Plk1 inhibitors killed CD133+ colon cancer cells leading to complete growth arrest of colon cancer stem cell‐derived xenografts, whereas chemotherapeutic agents only slowed tumor progression. While chemotherapy treatment increased CD133+ cell proliferation, treatment with Plk1 inhibitors eliminated all proliferating tumor‐initiating cells. Quiescent CD133+ cells that survived the treatment with Plk1 inhibitors could be killed by subsequent Plk1 inhibition when they exited from quiescence. Altogether, these results provide a new insight into the proliferative status of colon tumor‐initiating cells both in basal conditions and in response to therapy and indicate Plk1 inhibitors as potentially useful in the treatment of colorectal cancer. Stem Cells2012;30:1819–1830
Federica Francescangeli; Michele Patrizii; Michele Signore; Giulia Federici; Simone Di Franco; Alfredo Pagliuca; Marta Baiocchi; Mauro Biffoni; Lucia Ricci Vitiani; Matilde Todaro; Ruggero De Maria; Ann Zeuner. Proliferation State and Polo-Like Kinase1 Dependence of Tumorigenic Colon Cancer Cells. STEM CELLS 2012, 30, 1819 -1830.
AMA StyleFederica Francescangeli, Michele Patrizii, Michele Signore, Giulia Federici, Simone Di Franco, Alfredo Pagliuca, Marta Baiocchi, Mauro Biffoni, Lucia Ricci Vitiani, Matilde Todaro, Ruggero De Maria, Ann Zeuner. Proliferation State and Polo-Like Kinase1 Dependence of Tumorigenic Colon Cancer Cells. STEM CELLS. 2012; 30 (9):1819-1830.
Chicago/Turabian StyleFederica Francescangeli; Michele Patrizii; Michele Signore; Giulia Federici; Simone Di Franco; Alfredo Pagliuca; Marta Baiocchi; Mauro Biffoni; Lucia Ricci Vitiani; Matilde Todaro; Ruggero De Maria; Ann Zeuner. 2012. "Proliferation State and Polo-Like Kinase1 Dependence of Tumorigenic Colon Cancer Cells." STEM CELLS 30, no. 9: 1819-1830.
Prostate cancer is one of the leading causes of cancer-related death in men. Despite significant advances in prostate cancer diagnosis and management, the molecular events involved in the transformation of normal prostate cells into cancer cells have not been fully understood. It is generally accepted that prostate cancer derives from the basal compartment while expressing luminal markers. We investigated whether downregulation of the basal protein B-cell translocation gene 2 (BTG2) is implicated in prostate cancer transformation and progression. Here we show that BTG2 loss can shift normal prostate basal cells towards luminal markers expression, a phenotype also accompanied by the appearance of epithelial-mesenchymal transition (EMT) traits. We also show that the overexpression of microRNA (miR)-21 suppresses BTG2 levels and promotes the acquisition of luminal markers and EMT in prostate cells. Furthermore, by using an innovative lentiviral vector able to compete with endogenous mRNA through the overexpression of the 3'-untranslated region of BTG2, we demonstrate that in prostate tumor cells, the levels of luminal and EMT markers can be reduced by derepression of BTG2 from microRNA-mediated control. Finally, we show that the loss of BTG2 expression confers to non-tumorigenic prostate cells ability to grow in an orthotopic murine model, thus demonstrating the central role of BTG2 downregulaton in prostate cancer biology.
Vincenzo Coppola; Maria Musumeci; M Patrizii; A Cannistraci; Antonio Addario; Marcello Maugeri; Mauro Biffoni; Federica Francescangeli; Michelangelo Cordenonsi; Stephen R Piccolo; Lorenzo Memeo; A Pagliuca; Giovanni Muto; Ann Zeuner; Ruggero De Maria; Desiree Bonci. BTG2 loss and miR-21 upregulation contribute to prostate cell transformation by inducing luminal markers expression and epithelial–mesenchymal transition. Oncogene 2012, 32, 1843 -1853.
AMA StyleVincenzo Coppola, Maria Musumeci, M Patrizii, A Cannistraci, Antonio Addario, Marcello Maugeri, Mauro Biffoni, Federica Francescangeli, Michelangelo Cordenonsi, Stephen R Piccolo, Lorenzo Memeo, A Pagliuca, Giovanni Muto, Ann Zeuner, Ruggero De Maria, Desiree Bonci. BTG2 loss and miR-21 upregulation contribute to prostate cell transformation by inducing luminal markers expression and epithelial–mesenchymal transition. Oncogene. 2012; 32 (14):1843-1853.
Chicago/Turabian StyleVincenzo Coppola; Maria Musumeci; M Patrizii; A Cannistraci; Antonio Addario; Marcello Maugeri; Mauro Biffoni; Federica Francescangeli; Michelangelo Cordenonsi; Stephen R Piccolo; Lorenzo Memeo; A Pagliuca; Giovanni Muto; Ann Zeuner; Ruggero De Maria; Desiree Bonci. 2012. "BTG2 loss and miR-21 upregulation contribute to prostate cell transformation by inducing luminal markers expression and epithelial–mesenchymal transition." Oncogene 32, no. 14: 1843-1853.
Oncogene is one of the world’s leading cancer journals. It is published weekly and covers all aspects of the structure and function of Oncogenes.
Maria Musumeci; Vincenzo Coppola; Antonio Addario; M. Patrizii; Marcello Maugeri; Lorenzo Memeo; Cristina Colarossi; Federica Francescangeli; Mauro Biffoni; Devis Collura; Alessandro Giacobbe; L. D. Urso; Mario Falchi; Mary Anna Venneri; Giovanni Muto; Ruggero De Maria; Desiree Bonci. Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer. Oncogene 2011, 30, 4231 -4242.
AMA StyleMaria Musumeci, Vincenzo Coppola, Antonio Addario, M. Patrizii, Marcello Maugeri, Lorenzo Memeo, Cristina Colarossi, Federica Francescangeli, Mauro Biffoni, Devis Collura, Alessandro Giacobbe, L. D. Urso, Mario Falchi, Mary Anna Venneri, Giovanni Muto, Ruggero De Maria, Desiree Bonci. Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer. Oncogene. 2011; 30 (41):4231-4242.
Chicago/Turabian StyleMaria Musumeci; Vincenzo Coppola; Antonio Addario; M. Patrizii; Marcello Maugeri; Lorenzo Memeo; Cristina Colarossi; Federica Francescangeli; Mauro Biffoni; Devis Collura; Alessandro Giacobbe; L. D. Urso; Mario Falchi; Mary Anna Venneri; Giovanni Muto; Ruggero De Maria; Desiree Bonci. 2011. "Control of tumor and microenvironment cross-talk by miR-15a and miR-16 in prostate cancer." Oncogene 30, no. 41: 4231-4242.
International audienceStem Cell Factor (SCF), the ligand for the c-kit receptor, is essential for the production of red blood cells during development and stress erythropoiesis. SCF promotes erythroblast proliferation and survival, while delaying erythroid differentiation through mechanisms that are largely unknown. In cultures of primary human differentiating erythroblasts, we found that SCF induces an increase in the expression of Notch2, a member of the Notch family implicated in the control of cell growth and differentiation. Functional inhibition of either Notch or its ligand Jagged1 inhibited the effects of SCF on erythroid cell expansion. SCF induced also the expression of Hes-1 and GATA-2, that may contribute to transduce Notch2 signals in response to SCF. Transduction of primary erythroid precursors with a dominant negative Notch2 mutant inhibited both basal and SCF-mediated erythroblast expansion and counteracted the effects of SCF on erythroblast differentiation. These findings provide a clue to understand the effects of increased proliferation and delayed differentiation elicited by SCF on the erythroid compartment and indicate Notch2 as a new player in the regulation of red cell differentiation
Ann Zeuner; F Francescangeli; Michele Signore; Mary Anna Venneri; Francesca Pedini; Nadia Felli; A Pagliuca; C Conticello; R De Maria. The Notch2–Jagged1 interaction mediates stem cell factor signaling in erythropoiesis. Cell Death & Differentiation 2010, 18, 371 -380.
AMA StyleAnn Zeuner, F Francescangeli, Michele Signore, Mary Anna Venneri, Francesca Pedini, Nadia Felli, A Pagliuca, C Conticello, R De Maria. The Notch2–Jagged1 interaction mediates stem cell factor signaling in erythropoiesis. Cell Death & Differentiation. 2010; 18 (2):371-380.
Chicago/Turabian StyleAnn Zeuner; F Francescangeli; Michele Signore; Mary Anna Venneri; Francesca Pedini; Nadia Felli; A Pagliuca; C Conticello; R De Maria. 2010. "The Notch2–Jagged1 interaction mediates stem cell factor signaling in erythropoiesis." Cell Death & Differentiation 18, no. 2: 371-380.
Colorectal cancer stem cells (CR-CSC) are responsible for the generation and maintenance of intestinal tumors and are highly resistant to conventional chemotherapeutic agents. Aurora-A, a serine-threonine kinase involved in mitosis regulation, plays multiple key functions in tumor initiation and progression. We found that Aurora-A is overexpressed in primary colorectal tumor cells, in the CR-CSC fraction, and in stem cell–derived differentiated cells, compared with normal colon tissue. Aurora-A expression was functionally linked to centrosome amplification in CR-CSC, as indicated by the decrease in cells with multiple centrosomes that followed Aurora-A silencing. Knockdown of Aurora-A resulted in growth inhibition of CR-CSC, alteration of cell cycle kinetics, and downregulation of the expression levels of antiapoptotic Bcl-2 family members, strongly sensitizing to chemotherapy-induced cell death. Moreover, Aurora-A silencing compromised the ability to form tumor xenografts in immunocompromised mice and reduced the migratory capacity of CR-CSC. Altogether, these results indicate that Aurora-A is essential for CR-CSC regeneration and resistance to cytotoxic stimuli and suggest that therapies directed against Aurora-A may effectively target the stem cell population in colorectal cancer. Cancer Res; 70(11); 4655–65. ©2010 AACR.
Patrizia Cammareri; Alessandro Scopelliti; Matilde Todaro; Vincenzo Eterno; Federica Francescangeli; Mary Pat Moyer; Antonino Agrusa; Francesco Dieli; Ann Zeuner; Giorgio Stassi. Aurora-A Is Essential for the Tumorigenic Capacity and Chemoresistance of Colorectal Cancer Stem Cells. Cancer Research 2010, 70, 4655 -4665.
AMA StylePatrizia Cammareri, Alessandro Scopelliti, Matilde Todaro, Vincenzo Eterno, Federica Francescangeli, Mary Pat Moyer, Antonino Agrusa, Francesco Dieli, Ann Zeuner, Giorgio Stassi. Aurora-A Is Essential for the Tumorigenic Capacity and Chemoresistance of Colorectal Cancer Stem Cells. Cancer Research. 2010; 70 (11):4655-4665.
Chicago/Turabian StylePatrizia Cammareri; Alessandro Scopelliti; Matilde Todaro; Vincenzo Eterno; Federica Francescangeli; Mary Pat Moyer; Antonino Agrusa; Francesco Dieli; Ann Zeuner; Giorgio Stassi. 2010. "Aurora-A Is Essential for the Tumorigenic Capacity and Chemoresistance of Colorectal Cancer Stem Cells." Cancer Research 70, no. 11: 4655-4665.
An increased expression of antiapoptotic molecules is often found in malignant cells, where it contributes to their clonal expansion by conferring an improved survival ability. We found that erythroid precurors derived from patients with polycythemia vera (PV) with medium and high JAK2V617F mutation rates often express elevated levels of the antiapoptotic molecules Bcl-2 and Bcl-XL (5 of 12 patients with 3 to 7 times Bcl-2 and 3 of 12 patients with 4 to 7 times Bcl-XL than average normal controls) and are more resistant to myelosuppressive drugs than normal erythroblasts. ABT-737, a small-molecule inhibitor of Bcl-2, Bcl-XL, and Bcl-W, induced apoptosis preferentially in JAK2V617F-high PV erythroid precursors as compared with JAK2V617F-low or normal erythroblasts. ABT-737 inhibited also the proliferation of PV erythroblasts and interfered with the formation of endogenous erythroid colonies by PV hematopoietic progenitors. Altogether, these results suggest that small-molecule inhibitors of Bcl-2/Bcl-XL may be used in the treatment of patients with PV with high JAK2V617F allele burden.
Ann Zeuner; Francesca Pedini; Federica Francescangeli; Michele Signore; Gabriella Girelli; Agostino Tafuri; Ruggero De Maria. Activity of the BH3 mimetic ABT-737 on polycythemia vera erythroid precursor cells. Blood 2009, 113, 1522 -1525.
AMA StyleAnn Zeuner, Francesca Pedini, Federica Francescangeli, Michele Signore, Gabriella Girelli, Agostino Tafuri, Ruggero De Maria. Activity of the BH3 mimetic ABT-737 on polycythemia vera erythroid precursor cells. Blood. 2009; 113 (7):1522-1525.
Chicago/Turabian StyleAnn Zeuner; Francesca Pedini; Federica Francescangeli; Michele Signore; Gabriella Girelli; Agostino Tafuri; Ruggero De Maria. 2009. "Activity of the BH3 mimetic ABT-737 on polycythemia vera erythroid precursor cells." Blood 113, no. 7: 1522-1525.
The keratinocyte growth factor receptor (KGFR)/fibroblast growth factor receptor 2b is activated by high-affinity-specific interaction with two different ligands, keratinocyte growth factor (KGF)/fibroblast growth factor (FGF)7 and FGF10/KGF2, which are characterized by an opposite requirement of heparan sulfate proteoglycans and heparin for binding to the receptor. We investigated here the possible different endocytic trafficking of KGFR, induced by the two ligands. Immunofluorescence and immunoelectron microscopy analysis showed that KGFR internalization triggered by either KGF or FGF10 occurs through clathrin-coated pits. Immunofluorescence confocal microscopy using endocytic markers as well as tumor susceptibility gene 101 (TSG101) silencing demonstrated that KGF drives KGFR to the degradative pathway, while FGF10 targets the receptor to the recycling endosomes. Biochemical analysis showed that KGFR is ubiquitinated and degraded after KGF treatment but not after FGF10 treatment, and that the alternative fate of KGFR might depend on the different ability of the receptor to phosphorylate the fibroblast growth factor receptor substrate 2 (FRS2) substrate and to recruit the ubiquitin ligase c-Cbl. The recycling endocytic pathway followed by KGFR upon FGF10 stimulation correlates with the higher mitogenic activity exerted by this ligand on epithelial cells compared with KGF, suggesting that the two ligands may play different functional roles through the regulation of the receptor endocytic transport
Francesca Belleudi; Laura Leone; Valerio Nobili; Salvatore Raffa; Federica Francescangeli; Maddalena Maggio; Stefania Morrone; Cinzia Marchese; Maria Rosaria Torrisi. Keratinocyte Growth Factor Receptor Ligands Target the Receptor to Different Intracellular Pathways. Traffic 2007, 8, 1854 -1872.
AMA StyleFrancesca Belleudi, Laura Leone, Valerio Nobili, Salvatore Raffa, Federica Francescangeli, Maddalena Maggio, Stefania Morrone, Cinzia Marchese, Maria Rosaria Torrisi. Keratinocyte Growth Factor Receptor Ligands Target the Receptor to Different Intracellular Pathways. Traffic. 2007; 8 (12):1854-1872.
Chicago/Turabian StyleFrancesca Belleudi; Laura Leone; Valerio Nobili; Salvatore Raffa; Federica Francescangeli; Maddalena Maggio; Stefania Morrone; Cinzia Marchese; Maria Rosaria Torrisi. 2007. "Keratinocyte Growth Factor Receptor Ligands Target the Receptor to Different Intracellular Pathways." Traffic 8, no. 12: 1854-1872.