title: Sox2 is not required for melanomagenesis, melanoma growth and melanoma metastasis in vivo.
abstract: Melanoma is a dangerous form of skin cancer derived from the malignant transformation of melanocytes. The transcription factor SOX2 is not expressed in melanocytes, however, it has been shown to be differentially expressed between benign nevi and malignant melanomas and to be essential for melanoma stem cell maintenance and expansion in vitro and in xenograft models. By using a mouse model in which BRafV600Emutation cooperates with Pten loss to induce the development of metastatic melanoma, we investigated if Sox2 is required during the process of melanomagenesis, melanoma growth and metastasis and in the acquisition of resistance to BRAF inhibitors (BRAFi) treatments. We found that deletion of Sox2 specifically in Pten null and BRafV600E-expressing melanocytes did not prevent tumor formation and did not modify the temporal kinetics of melanoma occurrence compared to Sox2 wt mice. In addition, tumor growth was similar between Sox2 wt and Sox2 deleted (del) melanomas. By querying publicly available databases, we did not find statistically significant differences in SOX2 expression levels between benign nevi and melanomas, and analysis on two melanoma patient cohorts confirmed that Sox2 levels did not significantly change between primary and metastatic melanomas. Melanoma cell lines derived from both Sox2 genotypes showed a similar sensitivity to vemurafenib treatment and the same ability to develop vemurafenib resistance in long-term cultures. Development of vemurafenib resistance was not dependent on SOX2 expression also in human melanoma cell lines in vitro. Our findings exclude an oncogenic function for Sox2 during melanoma development and do not support a role for this transcription factor in the acquisition of resistance to BRAFi treatments.
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Cesarini
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Guida
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Todaro
authors.affiliation: Regina Elena National Cancer Institute - IFO, Oncogenomic and Epigenetic Unit, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Di Agostino
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Tassinari
authors.affiliation: Department of Biotechnology and Bioscience, University of Milan-Bicocca, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Nicolis
authors.affiliation: Department of Biotechnology and Bioscience, University of Milan-Bicocca, Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Favaro
authors.affiliation: Molecular Oncology Laboratory, Istituto Dermopatico dell'Immacolata - IRCCS, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Caporali
authors.affiliation: Molecular Oncology Laboratory, Istituto Dermopatico dell'Immacolata - IRCCS, Rome, Italy.
authors.forename: P M
authors.initials: PM
authors.lastname: Lacal
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Botti
authors.affiliation: Department of Biomedicine, Humanitas University, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Costanzo
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Rossi
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
authors.forename: E A
authors.initials: EA
authors.lastname: Jannini
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Dolci
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology / Q000556:secondary; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000502:physiology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D055748:SOXB1 Transcription Factors / Q000502:physiology*; D013449:Sulfonamides / Q000627:therapeutic use; D000077484:Vemurafenib
chemical_list: D007211:Indoles; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human