UCSF

Despite the global burden of prostate cancer, we lack an understanding of the genetic events that drive tumorigenesis and drug resistance, impeding the development of precision cancer medicine. Only a few genetic models of the disease exist, and of the limited number of prostate cancer cell lines, many lack androgen receptor expression and dependence, significantly curtailing their utility. Moreover, the lack of representation in genetic cohorts has led to systematic under-studying of genes more commonly mutated in populations of color, exacerbating racial and geographic healthcare disparities. To address these shortcomings, we developed a novel functional genomic system in which we induced mismatch repair deficiency in mouse prostate organoids with defined genetic backgrounds. In doing so, we generated heterogeneous pools of organoids that rapidly accumulated mutations, which we then injected into mice. Through this work, we determined how tumor genotype and treatment impacted the selective pressure on genomic alterations and the evolutionary trajectories of tumors. We also uncovered novel genetic drivers of tumorigenesis and drug resistance, all three of which have been profoundly understudied despite their prevalence in patients of African and Asian descent. Finally, we showed that we can generate a virtually unlimited number of ex vivo tumoroid lines and demonstrated their utility for further mechanistic study.