Investigating the impact of chromosomal instability on prostate cancer aggressiveness

PROJECT SUMMARY Prostate cancer (PC) is a leading cause of male cancer-related deaths. Once disseminated PC is incurable as it gradually progresses to all therapeutic options. The mechanisms underlying aggressive features and lethality of metastatic PC remain an unmet clinical need. We and others have reported that metastatic PC displays the highest levels of chromosomal instability (CIN), and we have shown that transcriptional reprogramming allows PC CIN-adaptation and survival in advanced disease. Yet, the molecular underpinnings of CIN impact on PC remain poorly understood. Using genetic, proteomic, epigenomics and high-resolution microscopy, we found that CIN is linked to transcriptional rewiring and bookmarking suggesting a role of CIN in cell reprogramming in lethal PC. High CIN PC remains highly dependent on mitotic fidelity programs like the ones controlled by MASTL kinase to restrain lethal catastrophic CIN levels. We find that MASTL regulates new late mitotic processes involved in centrosome biology and cytokinesis in PC cells. However, the substrates and effectors by which MASTL regulate these functions remain unknown. Finally, our in vivo data strongly suggest a relevant role of CIN impacting anti- tumor immunity in PC. In this application we will use unique genetic models to identify the substrates and cofactors by which MASTL kinase regulates new functions in high CIN PC (Aim 1). We will investigate the molecules and mechanisms underlying CIN-induced transcriptional reprogramming and gene bookmarking in PC (Aim 2) and will explore the tumor immune cell intrinsic and extrinsic mechanisms triggered by CIN in PC that may enhance immunotherapy efficacy (Aim 3). Through these studies we will mechanistically uncover novel aspects of CIN consequences for PC and may identify new potential treatment strategies for this lethal disease.