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Published on: July 21, 2018
A Functional Taxonomy of Tumor Suppression in Oncogenic KRAS-Driven Lung Cancer
Hongchen Cai1, Su Kit Chew2, Chuan Li3
1Department of Genetics, Stanford University School of Medicine, Stanford, California.
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.
Insights
Researchers identified new tumor suppressor genes that control cancer growth in a mouse model. Understanding these genes helps in developing new cancer therapies and interpreting genomic data.
Area of Science:
- Oncology
- Genetics
- Cancer Biology
Background:
- Cancer genotyping reveals numerous potential tumor suppressor genes, but their roles in carcinogenesis are often unclear.
- The multistep process of tumor initiation, growth, and progression involves complex genetic interactions.
- Understanding tumor suppressor gene function is crucial for cancer treatment and prevention strategies.
Purpose of the Study:
- To quantify the impact of 48 tumor suppressor genes on oncogenic KRAS-driven lung cancer using a multiplexed mouse model.
- To identify novel functional tumor suppressors that constrain cancer development *in vivo*.
- To elucidate the complex landscape of tumor suppression in cancer evolution.
Main Methods:
- Utilized a multiplexed mouse model for high-throughput, high-resolution genetic analysis of lung cancer.
- Quantified the effects of inactivating 48 known and putative tumor suppressor genes on various aspects of carcinogenesis.
- Analyzed tumor initiation, growth, and progression in response to specific gene alterations.
Main Results:
- Identified several previously understudied tumor suppressor genes that effectively constrain cancer growth *in vivo*.
- Demonstrated that inactivation of different tumor suppressor genes differentially impacts tumor initiation, overall growth, and the emergence of exceptionally large tumors.
- Uncovered novel genetic determinants influencing oncogenic KRAS-driven lung cancer initiation and progression.
Conclusions:
- The study reveals a complex and dynamic landscape of tumor suppression in lung cancer.
- Findings have significant implications for understanding cancer evolution and interpreting clinical cancer genome sequencing data.
- Highlights the value of quantitative *in vivo* genetic analyses in autochthonous cancer models for discovering therapeutic targets.
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