Promoterless Transposon Mutagenesis Drives Solid Cancers via Tumor Suppressor Inactivation

Author:

Aiderus, Aziz [ORCID]

Contreras-Sandoval, Ana M [ORCID]

Meshey, Amanda L

Newberg, Justin Y

Ward, Jerrold M

Swing,Debbie

Copeland, Neal G

Jenkins, Nancy A

Mann, Karen M [ORCID]

Mann, Michael B [ORCID]
Author Address

Department of Molecular Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA., Cancer Research Program, Houston Methodist Research Institute, Houston, TX 77030, USA., Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore., Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA., Departments of Gastrointestinal Oncology & Malignant Hematology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA., Cancer Biology and Evolution Program, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA., Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA., Donald A. Adam Melanoma and Skin Cancer Research Center of Excellence, Moffitt Cancer Center, Tampa, FL 33612, USA., Department of Cutaneous Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.,

Abstract:

A central challenge in cancer genomics is the systematic identification of single and cooperating tumor suppressor gene mutations driving cellular transformation and tumor progression in the absence of oncogenic driver mutation(s). Multiple in vitro and in vivo gene inactivation screens have enhanced our understanding of the tumor suppressor gene landscape in various cancers. However, these studies are limited to single or combination gene effects, specific organs, or require sensitizing mutations. In this study, we developed and utilized a Sleeping Beauty transposon mutagenesis system that functions only as a gene trap to exclusively inactivate tumor suppressor genes. Using whole body transposon mobilization in wild type mice, we observed that cumulative gene inactivation can drive tumorigenesis of solid cancers. We provide a quantitative landscape of the tumor suppressor genes inactivated in these cancers and show that, despite the absence of oncogenic drivers, these genes converge on key biological pathways and processes associated with cancer hallmarks.

See More

Author Address