Unbiased discovery and mechanistic interrogation of genetic drivers of malignant transformation

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Project Summary Cancer is a leading cause of death in the United States, causing hundreds of thousands of deaths each year. For the majority of these cases, tumors develop as a result of accumulated somatic mutations, of which thousands of clinically relevant combinations exist. To better understand this process the greater scientific and medical community has performed large-scale molecular profiling of patient samples. Such studies have identified a comprehensive catalog of molecular alterations in the cancer genome. However, the functional roles of many of these cancer genes still need to be explicitly tested in controlled experimental settings. Moreover, even fewer genes have been functionally probed for how they affect the tumor micro-environment (TME), an area of increasing interest and importance. It is therefore imperative to systematically and quantitatively assess the contribution of each gene on tumor progression and influence on the TME. To this end we leveraged an unbiased genome-scale CRISPR-Cas9 screen and identified and validated drivers of tumorigenesis in the in the context of liver hepatocellular carcinoma or (HCC). Of these drivers, Prkar1a, demonstrated robust tumor growth in validation experiments when knocked out in non-tumorigenic hepatocytes and transplanted into Nu/Nu mice. Additionally, Prkar1a’s role in liver cancer, or cancer more generally is not well understood. Therefore, we chose this gene for further mechanistic interrogation. In this proposal we will further probe the importance of Prkar1a for their role in liver tumorigenesis through two specific aims: AIM 1: Interrogate the molecular and cellular mechanism of ECM remodeling by Prkar1a AIM2: Develop clinically relevant models and dissect the immune landscape of Prkar1a-/- tumors. Together, these experiments will elucidate how Prkar1a knockout alters the TME, and promotes tumorigenesis in models of HCC. These findings will provide fundamental insights into Prkar1a-/- tumorigenesis, and assist in therapeutic development for these tumors.