Abstract A016: Mechanism of hypoxia-induced centrosome loss in early prostate cancer

Abstract

Abstract PURPOSE: We aim to understand cellular and microenvironmental determinants of chromosomal instability in prostate cancer and use these findings as prognostic biomarkers portending aggressive disease. Disease transitions during prostate cancer progression are accompanied by bursts of chromosomal instability (CIN), including chromosomal translocations, oncogene amplifications, and chromothripsis. While high CIN correlates with most metrics of aggressive disease, we lack a mechanistic understanding of how CIN originates in prostate cancer. Recently, we discovered that low Gleason score, primary prostate tumors lack centrosomes, cytoplasmic organelles that ensure the fidelity of chromosome segregation by organizing the shape of the mitotic spindle. Experimental elimination of centrosomes in immortalized, non-tumorigenic prostate cell lines was sufficient to generate extensive CIN resulting in oncogenic transformation of these lines when sub-cutaneously injected into NSG mice. Because we identified centrosome loss as a potential driver of CIN, we sought to understand mechanisms that can trigger centrosome loss in the prostate. Although centrosome loss naturally occurs during the development of some tissues, for example centrosome elimination during oogenesis, the mechanisms that trigger loss are not known. Therefore, we first investigated microenvironmental changes in early prostate cancer as a potential cause. Hypoxia, pathologically low oxygen concentration, is common in the aging prostate due to loss of vasculature and is associated with poor prostate cancer prognosis and high CIN. Therefore, we hypothesized that hypoxic exposure induces centrosome loss in prostate cells. Indeed, we found that exposure to 1% oxygen concentrations leads to progressive centrosome loss in non-tumorigenic, immortalized prostate epithelial cell lines. Using functional assays in cultured cells, we found that hypoxia-induced centrosome loss is an active disassembly process mediated by confluence-dependent Hippo signaling but independent of Hypoxia-Inducible Factor (HIF) transcription. We conclude that hypoxia-induced centrosome disassembly is a plausible driver of CIN in early prostate cancer. At present, we are developing immunohistochemistry assays to identify centrosome loss and hypoxia in biopsy samples to confirm these discoveries. Recently, we have described a combinatorial staining pattern (GLUT3/GLUT1/CA-9) that reliably identifies hypoxic tissue in patient-derived xenografts from prostate tumors. We are coupling this with a new assay to identify the structural component of the centrosome, called the centriole, which is identifiable during both mitosis and interphase. Together, our in situ assays will allow us to determine the penetrance of hypoxia-induced centrosome loss and its association with aggressive prostate cancer. Citation Format: John M. Ryniawec, Gregory C. Rogers, Anne E. Cress. Mechanism of hypoxia-induced centrosome loss in early prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A016.