Novel plasma exosome biomarkers for prostate cancer progression in co-morbid metabolic disease

• Published in: Advances in cancer biology - metastasis Vol. 6; p. 100073
• Main Authors: Jafari, Naser, Chen, Andrew, Kolla, Manohar, Pompa, Isabella R., Qiu, Yuhan, Yu, Rebecca, Llevenes, Pablo, Ennis, Christina S., Mori, Joakin, Mahdaviani, Kiana, Halpin, Meredith, Gignac, Gretchen A., Heaphy, Christopher M., Monti, Stefano, Denis, Gerald V.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2022; Elsevier
• Subjects: BET proteins; BRD4; Castration-resistant; Epigenetic regulators; Epithelial plasticity; Epithelial-mesenchymal transition; Next-generation BET degrader; Prostate cancer; BET proteins; Next-generation BET degrader; Epithelial plasticity; PROTAC; T2D; DAPI; EMT; PCA; BET; IFN; Epithelial-mesenchymal transition; ADT; TGF; Epigenetic regulators; FDR; FBS; ND; VST; PD-L1; Castration-resistant; IPA; Prostate cancer; BRD4; PSA
• ISSN: 2667-3940; 2667-3940
• DOI: 10.1016/j.adcanc.2022.100073

Comorbid Type 2 diabetes (T2D), a metabolic complication of obesity, associates with worse cancer outcomes for prostate, breast, head and neck, colorectal and several other solid tumors. However, the molecular mechanisms remain poorly understood. Emerging evidence shows that exosomes carry miRNAs in blood that encode the metabolic status of originating tissues and deliver their cargo to target tissues to modulate expression of critical genes. Exosomal communication potentially connects abnormal metabolism to cancer progression. Here, we hypothesized that T2D plasma exosomes induce epithelial-mesenchymal transition (EMT) and immune checkpoints in prostate cancer cells. We demonstrate that plasma exosomes from subjects with T2D induce EMT features in prostate cancer cells and upregulate the checkpoint genes CD274 and CD155. We demonstrate that specific exosomal miRNAs that are differentially abundant in plasma of T2D adults compared to nondiabetic controls (miR374a-5p, miR-93-5p and let-7b-3p) are delivered to cancer cells, thereby regulating critical target genes. We build on our previous reports showing BRD4 controls migration and dissemination of castration-resistant prostate cancer, and transcription of key EMT genes, to show that T2D exosomes require BRD4 to drive EMT and immune ligand expression. We validate our findings with gene set enrichment analysis of human prostate tumor tissue in TGCA genomic data. These results suggest novel, non-invasive approaches to evaluate and potentially block progression of prostate and other cancers in patients with comorbid T2D. •Human plasma exosomal microRNAs can reprogram prostate cancer cells, driving epithelial-to-mesenchymal transition (EMT).•Exosomal miRNA profiles differ between Type 2 diabetes and non-diabetic controls; T2D miRNAs are pro-metastatic.•These miRNAs are potential blood biomarkers for clinical decision making; men with T2D have high risk for biochemical progression.•Signatures correlate with TCGA genesets of primary and metastatic prostate cancer, to confirm clinical importance.•BET bromodomain proteins, particularly BRD4, regulate exosomal effector signaling, BET inhibitors can block this pathway.