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  • Book
    Zoë Natasha Rogers.
    Cancer genome sequencing has been instrumental in identifying the genomic alterations that occur in human tumors. The functional importance of the vast majority of these alterations, both alone and in combination, remains unknown and largely uninvestigated due to lack of tools enabling high-throughput interrogation of coincident genetic alterations in vivo. This thesis describes a method that integrates tumor barcoding with CRISPR/Cas9-mediated genome editing and ultra-deep barcode sequencing (Tuba-seq) to interrogate multiple tumor genotypes simultaneously in autochthonous mouse models of human cancer. I demonstrate the quantification of the effects of eleven of the most frequently inactivated genes in human lung adenocarcinoma and uncover the methyltransferase Setd2 and the splicing factor Rbm10 as novel suppressors of lung cancer growth. By quantifying the in vivo fitness advantage conferred by inactivation of each of these eleven genes in combination with inactivation of p53 or Lkb1, we identify unexpected context-dependent tumor suppression. I further demonstrate the ability of tumor barcoding to investigate clonal relationships between tumors and metastases, as well as uncover potential drugs to inhibit metastatic progression. These approaches will redefine our ability to understand how tumor suppressor inactivation impacts tumor initiation, growth, malignant transformation, and ultimately lead to the identification of therapy responses. Specifically, we can begin to investigate genotype specific drug responses and hope to inform a more precise and personalized era of patient care.