Transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression

Aziz Aiderus, Justin Y. Newberg, Liliana Guzman-Rojas, Ana M. Contreras- Sandoval, Amanda L. Meshey, Devin J. Jones, Felipe Amaya-Manzanares, Roberto Rangel, Jerrold M. Ward, Song Choon Lee, Kenneth Hon-Kim Ban, Keith Rogers, Susan M. Rogers, Luxmanan Selvanesan, Leslie A. McNoe, Neal G. Copeland, Nancy A. Jenkins, Kenneth Y. Tsai, Michael A. Black, Karen M. MannMichael B. Mann

Research output: Contribution to journalArticlepeer-review

Abstract

The systematic identification of genetic events driving cellular transformation and tumor progression in the absence of a highly recurrent oncogenic driver mutation is a challenge in cutaneous oncology. In cutaneous squamous cell carcinoma (cuSCC), the high UV-induced mutational burden poses a hurdle to achieve a complete molecular landscape of this disease. Here, we utilized the Sleeping Beauty transposon mutagenesis system to statistically define drivers of keratinocyte transformation and cuSCC progression in vivo in the absence of UV-IR, and identified both known tumor suppressor genes and novel oncogenic drivers of cuSCC. Functional analysis confirms an oncogenic role for the ZMIZ genes, and tumor suppressive roles for KMT2C, CREBBP and NCOA2, in the initiation or progression of human cuSCC. Taken together, our in vivo screen demonstrates an extremely heterogeneous genetic landscape of cuSCC initiation and progression, which can be harnessed to better understand skin oncogenic etiology and prioritize therapeutic candidates.

Original languageEnglish (US)
Article numbere1009094
JournalPLoS Genetics
Volume17
Issue number8
DOIs
StatePublished - Aug 16 2021

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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