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A Functional Taxonomy of Tumor Suppression in Oncogenic KRAS-Driven Lung Cancer

Cai, H; Chew, SK; Li, C; Tsai, MK; Andrejka, L; Murray, CW; Hughes, NW; ... Winslow, MM; + view all (2021) A Functional Taxonomy of Tumor Suppression in Oncogenic KRAS-Driven Lung Cancer. Cancer Discovery , 11 (7) pp. 1754-1773. 10.1158/2159-8290.CD-20-1325. Green open access

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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.

Type: Article
Title: A Functional Taxonomy of Tumor Suppression in Oncogenic KRAS-Driven Lung Cancer
Open access status: An open access version is available from UCL Discovery
DOI: 10.1158/2159-8290.CD-20-1325
Publisher version: https://doi.org/10.1158/2159-8290.CD-20-1325
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10137241
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