Endocrine Abstracts

Prostate Cancer (PC) affects 1-in-6 men in the UK, and obesity 1-in-3, with rates of both increasing. High-fat diet is linked with increased risk of PC death, and volume of peri-prostatic adipose tissue (PPAT) is associated with increased risk of lethal PC/reduced therapy response. Despite this, molecular mechanisms underpinning obesity-driven PC remain poorly-understood. This is important since weight-gain and central obesity are major side-effects of PC treatment using androgen-deprivation therapy. Adipose tissue (AT) shows altered secretory profiles in obese vs lean patients. This includes cytokines and extracellular-vesicles (EVs), which represent potential pro-tumourigenesis communication tools through delivery of proteins and non-coding RNAs such as microRNAs. Indeed, PPAT EVs promote ovarian and breast cancer progression and contain abundant small RNAs, but near-absence of mRNA/DNA. This project investigates EV-mediated mechanisms of communication between PPAT and PC epithelial cells, and their clinical implications. We optimised primary PPAT explant culture and in vitro adipocyte differentiation, and comprehensively characterised PPAT EVs. PPAT EVs from obese patients significantly increased proliferation and migration of PC cells but reduced angiogenesis compared to EVs from lean patients, consistent with elevated hypoxia observed in AT in obesity. We also observed reduced levels of angiogenesis-promoting cytokines in conditioned medium of obese vs lean PPAT. Small RNA-seq analysis identified 48 significantly-altered microRNAs in PPAT EVs from obese vs lean patients, with targets over-represented in MAPK signalling and actin cytoskeleton. Further, PPAT-derived EVs significantly altered the PC cell transcriptome: obese vs lean PPAT EV differentially-modulated pathways include Rac/Rho, Wnt and EGFR signalling and actin cytoskeleton. Top PPAT EV-dysregulated genes are increased in PC vs normal tissue and are associated with reduced survival. Anti-tumourigenic cytokines are decreased in conditioned medium of obese vs lean PC patient PPAT. Integrative analysis of these data will elucidate novel, actionable drivers of PC progression for personalised medicine.