MYC-driven increases in mitochondrial DNA copy number occur early and persist throughout prostatic cancer progression

Abstract

Increased mitochondrial function may render some cancers vulnerable to mitochondrial inhibitors. Since mitochondrial function is regulated partly by mitochondrial DNA copy number (mtDNAcn), accurate measurements of mtDNAcn could help reveal which cancers are driven by increased mitochondrial function and may be candidates for mitochondrial inhibition. However, prior studies have employed bulk macrodissections that fail to account for cell type–specific or tumor cell heterogeneity in mtDNAcn. These studies have often produced unclear results, particularly in prostate cancer. Herein, we developed a multiplex in situ method to spatially quantify cell type–specific mtDNAcn. We show that mtDNAcn is increased in luminal cells of high-grade prostatic intraepithelial neoplasia (HGPIN), is increased in prostatic adenocarcinomas (PCa), and is further elevated in metastatic castration-resistant prostate cancer. Increased PCa mtDNAcn was validated by 2 orthogonal methods and is accompanied by increases in mtRNAs and enzymatic activity. Mechanistically, MYC inhibition in prostate cancer cells decreases mtDNA replication and expression of several mtDNA replication genes, and MYC activation in the mouse prostate leads to increased mtDNA levels in the neoplastic prostate cells. Our in situ approach also revealed elevated mtDNAcn in precancerous lesions of the pancreas and colon/rectum, demonstrating generalization across cancer types using clinical tissue samples.

Overexpression of Fibroblast Activation Protein (FAP) in stroma of proliferative inflammatory atrophy (PIA) and primary adenocarcinoma of the prostate

“…In carcinoma, the FAP area fraction was also increased, compared with normal appearing regions, albeit it was not as high as in PIA. Exploring mRNA expression data from a recent study (The JHU LCM Prostatectomy Dataset) from our group using laser capture microdissection, 43 FAP was overexpressed in tumor regions compared with matched normal regions ( Supplemental Fig. 2 ).…”

“… A , Data from MSKCC Cancer Cell 45 (N = 131 samples from primary tumors with mRNA). B , Data from Chen et al, Johns Hopkins, JCI Insight 43 (N = 126 samples from 120 patients). C , Data from TCGA, Cell, 2015 65 (N = 290 samples/patients).…”