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A cellular model reflecting the phenotypic heterogeneity of mutant HRAS driven squamous cell carcinoma
Author(s) -
Cantariño Neus,
FernándezFigueras M. Teresa,
Valero Vanesa,
Musulén Eva,
Malinverni Roberto,
Granada Isabel,
Goldie Stephen J.,
MartínCaballero Juan,
Douet Julien,
Forcales SoniaVanina,
Buschbeck Marcus
Publication year - 2016
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30139
Subject(s) - hras , biology , cancer research , phenotype , genetic heterogeneity , telomerase , cell culture , cell , mutant , kras , telomerase reverse transcriptase , mutation , pathology , genetics , medicine , gene
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.