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. Mann; Michael B. Mann

doi:10.1371/journal.pgen.1009094

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 journal › Article › peer-review

4 Scopus citations

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 language	English (US)
Article number	e1009094
Pages (from-to)	e1009094
Journal	PLoS Genetics
Volume	17
Issue number	8
DOIs	https://doi.org/10.1371/journal.pgen.1009094
State	Published - Aug 16 2021

Keywords

Biomarkers, Tumor/genetics
CREB-Binding Protein/genetics
Carcinoma, Squamous Cell/genetics
Cell Transformation, Neoplastic/genetics
DNA Transposable Elements
DNA-Binding Proteins/genetics
Disease Progression
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
High-Throughput Nucleotide Sequencing
Humans
Keratinocytes/pathology
Mutagenesis, Insertional/methods
Nuclear Receptor Coactivator 2/genetics
Sequence Analysis, DNA/methods
Skin Neoplasms/genetics

ASJC Scopus subject areas

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

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Aiderus, A., Newberg, J. Y., Guzman-Rojas, L., Contreras- Sandoval, A. M., Meshey, A. L., Jones, D. J., Amaya-Manzanares, F., Rangel, R., Ward, J. M., Lee, S. C., Hon-Kim Ban, K., Rogers, K., Rogers, S. M., Selvanesan, L., McNoe, L. A., Copeland, N. G., Jenkins, N. A., Tsai, K. Y., Black, M. A., ... Mann, M. B. (2021). Transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression. PLoS Genetics, 17(8), e1009094. Article e1009094. https://doi.org/10.1371/journal.pgen.1009094

Aiderus, A, Newberg, JY, Guzman-Rojas, L, Contreras- Sandoval, AM, Meshey, AL, Jones, DJ, Amaya-Manzanares, F, Rangel, R, Ward, JM, Lee, SC, Hon-Kim Ban, K, Rogers, K, Rogers, SM, Selvanesan, L, McNoe, LA, Copeland, NG , Jenkins, NA, Tsai, KY, Black, MA, Mann, KM & Mann, MB 2021, 'Transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression', PLoS Genetics, vol. 17, no. 8, e1009094, pp. e1009094. https://doi.org/10.1371/journal.pgen.1009094

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title = "Transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression",

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.",

keywords = "Biomarkers, Tumor/genetics, CREB-Binding Protein/genetics, Carcinoma, Squamous Cell/genetics, Cell Transformation, Neoplastic/genetics, DNA Transposable Elements, DNA-Binding Proteins/genetics, Disease Progression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, High-Throughput Nucleotide Sequencing, Humans, Keratinocytes/pathology, Mutagenesis, Insertional/methods, Nuclear Receptor Coactivator 2/genetics, Sequence Analysis, DNA/methods, Skin Neoplasms/genetics",

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

note = "Publisher Copyright: {\textcopyright} 2021 Aiderus et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2021",

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doi = "10.1371/journal.pgen.1009094",

language = "English (US)",

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T1 - Transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression

AU - Aiderus, Aziz

AU - Newberg, Justin Y.

AU - Guzman-Rojas, Liliana

AU - Contreras- Sandoval, Ana M.

AU - Meshey, Amanda L.

AU - Jones, Devin J.

AU - Amaya-Manzanares, Felipe

AU - Rangel, Roberto

AU - Ward, Jerrold M.

AU - Lee, Song Choon

AU - Hon-Kim Ban, Kenneth

AU - Rogers, Keith

AU - Rogers, Susan M.

AU - Selvanesan, Luxmanan

AU - McNoe, Leslie A.

AU - Copeland, Neal G.

AU - Jenkins, Nancy A.

AU - Tsai, Kenneth Y.

AU - Black, Michael A.

AU - Mann, Karen M.

AU - Mann, Michael B.

N1 - Publisher Copyright: © 2021 Aiderus et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2021/8/16

Y1 - 2021/8/16

N2 - 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.

AB - 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.

KW - Biomarkers, Tumor/genetics

KW - CREB-Binding Protein/genetics

KW - Carcinoma, Squamous Cell/genetics

KW - Cell Transformation, Neoplastic/genetics

KW - DNA Transposable Elements

KW - DNA-Binding Proteins/genetics

KW - Disease Progression

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Keratinocytes/pathology

KW - Mutagenesis, Insertional/methods

KW - Nuclear Receptor Coactivator 2/genetics

KW - Sequence Analysis, DNA/methods

KW - Skin Neoplasms/genetics

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AN - SCOPUS:85113407837

SN - 1553-7390

VL - 17

SP - e1009094

JO - PLoS Genetics

JF - PLoS Genetics

IS - 8

M1 - e1009094

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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