Extracellular-vesicles from the peri-prostatic adipose tissue of obese, but not lean, men promote prostate cancer aggressivity

Nil Grunberg; Jiani Qian; Tam Joseph; Marc Lorentzen; Sila Akdogan; Nathan Lack; Moray Campbell; Cory Abate-Shen; Bijan Khoubehi; Taimur Shah; Mathias Winkler; Hashim Ahmed; Charlotte Bevan; Claire Fletcher

doi:10.1530/endoabs.109.S3.2

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Endocrine Abstracts (2025) 109 S3.2 | DOI: 10.1530/endoabs.109.S3.2

SFEBES2025 Symposia The adipose microenvironment: the missing link between obesity and cancer? (3 abstracts)

Extracellular-vesicles from the peri-prostatic adipose tissue of obese, but not lean, men promote prostate cancer aggressivity

Nil Grunberg ¹ , Jiani Qian ¹ , Tam Joseph ¹ , Marc Lorentzen ¹ , Sila Akdogan ² , Nathan Lack ^2,3 , Moray Campbell ⁴ , Cory Abate-Shen ⁵ , Bijan Khoubehi ⁶ , Taimur Shah ⁶ , Mathias Winkler ⁶ , Hashim Ahmed ⁶ , Charlotte Bevan ¹ & Claire Fletcher ¹

Author affiliations

¹Imperial College London, London, United Kingdom. ²Koc University, Istanbul, Turkey. ³Vancouver Prostate Center, Vancouver, Canada. ⁴Cedars-Sinai Medical Center, Los Angeles, USA. ⁵Columbia University, New York, USA. ⁶Imperial College NHS Trust, London, United Kingdom

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%. The peri-prostatic adipose tissue (PPAT), volume of which is associated with PC lethality/reduced therapy response, is an important component of the PC tumour-microenvironment. Adipose-tissue (AT) is the largest human endocrine gland, showing an altered 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 tumour 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/tumour tissue and clinical information. We showed that PPAT EVs from obese but not lean patients, significantly increase proliferation and migration of PC cells in vitro. Obese PPAT EVs also reduce angiogenesis, consistent with chronic hypoxia observed in obese patient adipose. We performed small RNA-seq on PPAT EVs from obese/lean PC patients, and mRNA-seq on PC cells treated with these EVs. Top PPAT-EV dysregulated genes are associated with PC survival. Silencing of one such PPAT-upregulated gene, TBX1, repressed PC cell aggressiveness in vitro. 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 in PPAT of aggressive-versus-indolent tumours. Integrative analysis of these data will hopefully elucidate novel, actionable drivers of aggressive PC progression for personalized-medicine.