A Functional Taxonomy of Tumor Suppression in Oncogenic KRAS–Driven Lung Cancer
Year: 2021
Type: article
Abstract: Cancer genotyping has identified a large number of putative tumor suppressor genes. Carcinogenesis is a multistep process, but the importance and specific roles of many of these genes during tumor initiation, growth, and progression remain unknown. Here we use a multiplexed mouse model of oncogenic KRAS–driven lung cancer to quantify the impact of 48 known and putative tumor suppressor genes on diverse aspects of carcinogenesis at an unprecedented scale and resolution. We uncover many previously understudied functional tumor suppressors that constrain cancer in vivo. Inactivation of some genes substantially increased growth, whereas the inactivation of others increases tumor initiation and/or the emergence of exceptionally large tumors. These functional in vivo analyses revealed an unexpectedly complex landscape of tumor suppression that has implications for understanding cancer evolution, interpreting clinical cancer genome sequencing data, and directing approaches to limit tumor initiation and progression. Significance: Our high-throughput and high-resolution analysis of tumor suppression uncovered novel genetic determinants of oncogenic KRAS–driven lung cancer initiation, overall growth, and exceptional growth. This taxonomy is consistent with changing constraints during the life history of cancer and highlights the value of quantitative in vivo genetic analyses in autochthonous cancer models. This article is highlighted in the In This Issue feature, p. 1601
Source: Cancer Discovery
Authors: Hongchen Cai, Su Kit Chew, Chuan Li, Min K. Tsai, Laura Andrejka, Christopher W. Murray, Nicholas W. Hughes, Emily G. Shuldiner, Emily L. Ashkin, Rui Tang, King L. Hung, Leo C. Chen, Shi Ya C. Lee, Maryam Yousefi, Wen-Yang Lin, Christian A. Kunder, Le Cong, Christopher D. McFarland, Dmitri A. Petrov, Charles Swanton, Monte M. Winslow
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: hybrid
Funders: Damon Runyon Cancer Research Foundation, Tobacco-Related Disease Research Program, Wellcome Trust, Francis Crick Institute, Cancer Research UK, Rosetrees Trust, National Institutes of Health, Medical Research Council, European Research Council, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences
Awards: G120984652, G1872847433, G1877678424, G1996051669, G2646115653, G2721152307, Quantifying the sources and dynamics of tumor growth variability using Tuba-seq, G3486387481, (PQ4) Quantitative and multiplexed analysis of gene function in cancer in vivo, A Quantitative Multiplexed Platform for the Pharmacogenomic Analysis of Lung Cancer, Quantifying the sources and dynamics of tumor growth variability using Tuba-seq, G6774517903, G6923477830, G7334899787, Unraveling mechanisms of tumor suppression in lung cancer, G8002126811, G8003459845, G8634521478, Molecular dissection of Lkb1-mediated tumor suppression, G8863471701, G8866839357, Therapeutic dissection of genotype-specific lung cancer vulnerabilities, Stanford Cancer Institute, Leveraging innovative technologies in basic and clinical cancer research, Institutional Training Grant in Genome Science, Towards Robust Multiplex Genome Engineering Beyond CRISPR-Cas9, Genomics of rapid adaptation in the lab and in the wild
OpenAlex ID: W3130366704