title: A cellular model reflecting the phenotypic heterogeneity of mutant HRAS driven squamous cell carcinoma.
abstract: Squamous cell carcinomas have a range of histopathological manifestations. The parameters that determine this clinically observed heterogeneity are not fully understood. Here, we report the generation of a cell culture model that reflects part of this heterogeneity. We have used the catalytic subunit of human telomerase hTERT and large T to immortalize primary UV-unexposed keratinocytes. Then, mutant HRAS G12V has been introduced to transform these immortal keratinocytes. When injected into immunosuppressed mice, transformed cells grew as xenografts with distinct histopathological characteristics. We observed three major tissue architectures: solid, sarcomatoid and cystic growth types, which were primarily composed of pleomorphic and basaloid cells but in some cases displayed focal apocrine differentiation. We demonstrate that the cells generated represent different stages of skin cancerogenesis and as such can be used to identify novel tumor-promoting alterations such as the overexpression of the PADI2 oncogene in solid-type SCC. Importantly, the cultured cells maintain the characteristics from the xenograft they were derived from while being amenable to manipulation and analysis. The availability of cell lines representing different clinical manifestations opens a new tool to study the stochastic and deterministic factors that cause case-to-case heterogeneity despite departing from the same set of oncogenes and the same genetic background.
authors.affiliation: Institute of Predictive and Personalized Medicine of Cancer, Campus Can Ruti, Badalona, Spain.
authors.forename: Neus
authors.initials: N
authors.lastname: Cantariño
authors.affiliation: Department Of Pathology, Hospital Universitari Germans Trias I Pujol, Campus Can Ruti, Badalona, Spain.
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Fernández-Figueras
authors.affiliation: Institute of Predictive and Personalized Medicine of Cancer, Campus Can Ruti, Badalona, Spain.|Josep Carreras Leukaemia Research Institute (IJC), Campus ICO - Germans Trias I Pujol, (IJC), Campus Can Ruti, Badalona, Spain.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Valero
authors.affiliation: Department Of Pathology, Hospital Universitari Germans Trias I Pujol, Campus Can Ruti, Badalona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Musulén
authors.affiliation: Institute of Predictive and Personalized Medicine of Cancer, Campus Can Ruti, Badalona, Spain.|Josep Carreras Leukaemia Research Institute (IJC), Campus ICO - Germans Trias I Pujol, (IJC), Campus Can Ruti, Badalona, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Malinverni
authors.affiliation: Josep Carreras Leukaemia Research Institute (IJC), Campus ICO - Germans Trias I Pujol, (IJC), Campus Can Ruti, Badalona, Spain.|Department of Hematology, Instituto Catalán De Oncología (ICO) - Hospital Universitari Germans Trias I Pujol, Universitat Autònoma De Barcelona, Campus Can Ruti, Badalona, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Granada
authors.affiliation: Li KaShing Centre, Cancer Research UK Cambridge Research Institute, Robinson Way, Cambridge, CB2 0RE, United Kingdom.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Goldie
authors.affiliation: Animal Facility, PRBB, Barcelona, 08003, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Martín-Caballero
authors.affiliation: Josep Carreras Leukaemia Research Institute (IJC), Campus ICO - Germans Trias I Pujol, (IJC), Campus Can Ruti, Badalona, Spain.
authors.forename: Julien
authors.initials: J
authors.lastname: Douet
authors.affiliation: Institute of Predictive and Personalized Medicine of Cancer, Campus Can Ruti, Badalona, Spain.
authors.forename: Sonia-Vanina
authors.initials: SV
authors.lastname: Forcales
authors.affiliation: Institute of Predictive and Personalized Medicine of Cancer, Campus Can Ruti, Badalona, Spain.|Josep Carreras Leukaemia Research Institute (IJC), Campus ICO - Germans Trias I Pujol, (IJC), Campus Can Ruti, Badalona, Spain.
authors.forename: Marcus
authors.initials: M
authors.lastname: Buschbeck
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D056726:Genetic Association Studies; D064593:Heterografts; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009154:Mutation; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: cell culture and xenograft model; squamous cell carcinoma; tumour heterogeneity