LAUSR

Extensive cancer genotyping has identified a large number of putative tumor-suppressor genes. However, genome sequencing data alone are insufficient to uncover the importance and role of these genes during carcinogenesis. Moreover, whether tumor suppressors restrict the rate of tumor growth, decrease the probability of incipient tumorigenesis, or limit the emergence of particularly fast-growing clones remains unknown for even the most well-studied tumor suppressors. I will discuss the development and use of multiplexed autochthonous mouse models of human lung adenocarcinoma that integrate tumor barcoding, CRISPR/Cas9-based genome editing, and high-throughput barcode sequencing (Tuba-seq). Using these methods, the impact of large panels of putative tumor suppressor genes can be quantified in parallel. We find that many previously understudied genes have strong effects on multiple aspects of tumor growth in vivo. While some functional tumor-suppressor genes have particularly strong effects only during some but not other phases of tumorigenesis, many genes impacted multiple facets of cancer development. Tuba-seq-based studies across oncogenic contexts and with combinatorial tumor suppressor gene inactivation further highlight the context dependency of gene function during carcinogenesis. These cause-and-effect analyses uncover an unexpectedly complex taxonomy of tumor suppression. We have further employed these multiplexed and quantitative in vivo models to assess the relationship between tumor genotype and therapeutic responses at scale. We coupled Tuba-seq with robust statistical methods to enable the generation of a pharmacogenomic map of lung cancer treatment responses in vivo. We uncover a surprisingly informative map of genotype-specific therapeutic responses, which highlights the importance of tumor-suppressor genotype in driving precision treatment approaches. These blueprints of the multifaceted nature of carcinogenesis have implications for understanding cancer evolution, interpreting clinical cancer genome sequencing data, and directing approaches for precision cancer treatment. Citation Format: Hongchen Cai, Chuan Li, Su Kit Chew, Maryam Yousefi, Giorgia Foggetti, Wen-Yang Lin, Zoe N. Rogers, Ian P. Winters, Christopher D. McFarland, Katherina Politi, Charlie Swanton, Dmitri A. Petrov, Monte M. Winslow. Multiplexed functional cancer genomics [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr IA26.