OR30-05 Communication between prostate tumours and periprostatic adipose drives obesity associated prostate cancer aggressivity

Résumé fourni par la source

Abstract Disclosure: N. Grunberg: None. J. Qian: None. J. Tam: None. M. Lorentzen: None. S. Akdogan: None. N. Lack: None. M. Campbell: None. C. Abate-Shen: None. D. Leach: None. B. Khoubehi: None. T. Shah: None. M. Winkler: None. A. Hashim: None. C. Bevan: None. C. Fletcher: None. Prostate cancer (PC) affects 1-in-8-men and obesity, termed a global epidemic by the WHO, affects 1-in-3. Obesity is the largest modifiable cancer risk-factor: every five-point increase in body-mass index increases risk of fatal PC by almost 10% and shortens the time to development of treatment-refractory metastatic disease. Further, weight gain is a common side-effect of mainstay androgen-deprivation therapy. The peri-prostatic adipose tissue (PPAT) is an important component of the PC tumor microenvironment (TME). PPAT volume is associated with increased PC lethality/reduced therapy response. Additionally, adipose tissue (AT) is the largest human endocrine gland, showing an altered (potentially pro-tumor) secretome in obesity. PPAT can also secrete extracellular-vesicles (EVs) carrying cargo including microRNAs, which are involved in melanoma, lung, ovarian and breast cancer progression. Despite accumulating evidence showing the importance of AT secretome in tumor growth, its roles in PC progression are still poorly understood. This project investigates EV-mediated mechanisms of communication between PPAT and PC epithelial cells, and their clinical implications. To date, we established a biobank from >120 patients, with matching PPAT, tumor tissue, clinical information and MRI scans. Functionally, we showed that PPAT EVs from obese but not lean patients, significantly increase proliferation and migration of PC cells in vitro. Non-prostatic adipose (NPAT) is unable to recapitulate these effects. Obese PPAT EVs also reduce angiogenesis, consistent with chronic hypoxia observed in obese patient adipose, suggesting a switch to non-oxidative metabolism in PC to meet increasing energy demands. We performed small RNA-seq on PPAT EVs from obese and lean PC patients, and mRNA-seq on PC cells treated with these EVs. These analyses revealed dysregulation of cellular metabolism and extracellular-matrix (ECM) remodeling by PPAT EVs. Top PPAT-EV dysregulated genes are associated with PC survival and are increased in PC vs normal tissue. Silencing of one such PPAT-upregulated gene, TBX1, repressed PC cell migration, invasion, proliferation and EMT. We also optimized in vitro adipocyte differentiation from PPAT stem cells to demonstrate that PPAT effects are specifically attributable to mature-adipocytes. Finally, we showed that RNA-seq analysis of PPAT from genetically-engineered mouse models (GEMMs) modelling PC natural history, showed dramatic changes in tissue histology, immune response, lipid metabolism and ECM genes in PPAT of aggressive-versus-indolent tumours. Since genetic alterations in GEMMs are prostate-confined, such transcriptomic changes must be mediated by paracrine signalling from PC cells. Integrative analysis of these data may elucidate novel, actionable drivers of aggressive PC progression for personalized medicine. Presentation: Monday, July 14, 2025

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.