A Functional Taxonomy of Tumor Suppression in Oncogenic KRAS-Driven Lung Cancer
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...
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Published in | Cancer discovery Vol. 11; no. 7; pp. 1754 - 1773 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
01.07.2021
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Subjects | |
Online Access | Get full text |
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Summary: | 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
. 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
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
genetic analyses in autochthonous cancer models.
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Bibliography: | CONTRIBUTIONS These authors contributed equally H.C., S.K.C., C.L., M.M.W., C.S., and D.A.P. designed the project. H.C. and S.K.C. generated the lentiviral vector pool and initiated lung tumors in mice. H.C, M.K.T. and R.T. bred the mice. H.C., S.K.C., C.L., M.K.T., L.A., C.W.M., R.T., K.L.H., L.C.C. and M.Y. collected lung samples. L.A., E.L.A. and K.L.H. performed immunohistochemical staining. H.C., S.K.C., L.A., C.W.M. and W.Y.L. generated the barcode sequencing library. C.L. and E.G.S. analyzed the Tuba-seq data. N.W.H. and L.C. analyzed DepMap and indel data. S.K.C., L.C.C., S.Y.C.L. and C.D.M. analyzed the human datasets. C.A.K. analyzed the tumor histology. H.C., S.K.C., C.L., D.A.P. and M.M.W. wrote the manuscript with comments from all authors. |
ISSN: | 2159-8274 2159-8290 |
DOI: | 10.1158/2159-8290.CD-20-1325 |