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

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

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 hurdl...

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Autores principales: 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 Mann, Michael B Mann
Formato: article
Lenguaje:EN
Publicado: Public Library of Science (PLoS) 2021
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Genetics
QH426-470
Acceso en línea:https://doaj.org/article/9ca296e0d3ca42438be6049b510b1dcf
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spelling oai:doaj.org-article:9ca296e0d3ca42438be6049b510b1dcf2021-12-02T20:03:23ZTransposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression.1553-73901553-740410.1371/journal.pgen.1009094https://doaj.org/article/9ca296e0d3ca42438be6049b510b1dcf2021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009094https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404The 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.Aziz AiderusJustin Y NewbergLiliana Guzman-RojasAna M Contreras-SandovalAmanda L MesheyDevin J JonesFelipe Amaya-ManzanaresRoberto RangelJerrold M WardSong-Choon LeeKenneth Hon-Kim BanKeith RogersSusan M RogersLuxmanan SelvanesanLeslie A McNoeNeal G CopelandNancy A JenkinsKenneth Y TsaiMichael A BlackKaren M MannMichael B MannPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 8, p e1009094 (2021)
institution DOAJ
collection DOAJ
language EN
topic Genetics
QH426-470
spellingShingle Genetics
QH426-470
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 Mann
Michael B Mann
Transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression.
description 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.
format article
author 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 Mann
Michael B Mann
author_facet 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 Mann
Michael B Mann
author_sort Aziz Aiderus
title Transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression.
title_short Transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression.
title_full Transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression.
title_fullStr Transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression.
title_full_unstemmed Transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression.
title_sort transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression.
publisher Public Library of Science (PLoS)
publishDate 2021
url https://doaj.org/article/9ca296e0d3ca42438be6049b510b1dcf
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