Abstract 3772: Increased mitochondrial gene expression in prostate cancer

Abstract

Abstract Warburg postulated that aerobic glycolysis, which is commonly observed in cancer, results from crippled mitochondrial function. Yet, most cancers and other rapidly proliferating cells rely on a functioning mitochondrial TCA cycle to generate important biosynthetic intermediates required for cell growth, and on the electron transport chain for pyrimidine synthesis and to recycle electron acceptors. Thus, increases in a number of mitochondrial activities have been proposed to be required for robust proliferation in most cancers. Mitochondrial function is regulated in part through mitochondrial biogenesis, which is influenced by mitochondrial DNA copy number (mtDNAcn). We previously developed an in situ hybridization method to quantify mtDNAcn in specific cell compartments in relation to normal physiological functioning and disease processes. We reported marked cell type heterogeneity across normal tissues including relatively higher mtDNAcn in a number of stem/proliferative compartments in humans and mice (PMID: 32304697). More recently, we combined this in situ approach with immunohistochemistry and reported increased mtDNAcn along with widespread heterogeneity in prostate cancer (DOI: 10.1158/1538-7445.AM2021-2404). We also found increased mtDNAcn in high grade prostatic intraepithelial neoplasia, the main precursor to prostate cancer, as well as precursor lesions in the large intestine and pancreas. To interrogate the functional significance of this mtDNAcn alteration, we sought to determine whether increased and heterogeneous mtDNAcn levels are accompanied by corresponding changes in its gene expression (mtRNA). To establish an initial survey of the landscape of steady state mtRNA levels, we used the RNAscope HiPlex system for multiplex in situ hybridization for 4 different mtRNAs along with in situ hybridization for mtDNA and combined this with immunofluorescence. In normal prostatic epithelium, we observed that the overall mtRNA expression pattern correlated with mtDNAcn, with higher levels in the basal cell layer compared with the luminal cell layer. We also found that, similar to changes in mtDNAcn in invasive prostate cancer, the 4 mtRNAs were upregulated yet heterogeneous in cancer lesions. Among the invasive tumors, cribriform prostate cancer showed distinct mtDNA and mtRNAs expression patterns, with higher signals in the peripheral cells than central cells, suggesting underlying biological differences in this unique histologic pattern. This spatial pattern in cribriform lesions correlated with the pattern of MYC protein expression, which is known to regulate mitochondrial biogenesis. Overall, we present a novel approach that advances the ability to quantify mtDNAcn and mtRNAs simultaneously in specific cell types while preserving the tissue spatial context. These findings suggest that increased mitochondrial function accompanies prostate cancer development and progression. Citation Format: Jiayu Chen, Qizhi Zheng, Jessica L. Hicks, Levent Trabzonlu, Ibrahim Kulac, Alan K. Meeker, Srinivasan Yegnasubramanian, Angelo M. De Marzo. Increased mitochondrial gene expression in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3772.