Peri-prostatic adipose tissue drives obesity-associated prostate cancer aggressivity via extracellular vesicles and Rho GTPase signalling

Nil Grunberg; Jiani Qian; Joseph Tam; Karen Nyga; Marc Lorentzen; Sila Akdogan; Nathan Lack; Moray Campbell; Corinne Abate-Shen; Bijan Khoubehi; Giles Hellawell; Taimur Shah; Mathias Winkler; Damien Leach; Hashim Ahmed; Charlotte Bevan; Claire Fletcher

doi:10.1530/endoabs.117.OC2.1

OC2.1

Prev Next

Section Contents Cite

Endocrine Abstracts (2026) 117 OC2.1 | DOI: 10.1530/endoabs.117.OC2.1

SFEBES2026 Oral Communications Mechanisms and Management of Endocrine Disease (5 abstracts)

Peri-prostatic adipose tissue drives obesity-associated prostate cancer aggressivity via extracellular vesicles and Rho GTPase signalling

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

Author affiliations

¹Imperial College London, London, United Kingdom; ²Koc University, Istanbul, Turkey; ³Vancouver Prostate Center, Vancouver, Canada; ⁴Karmanos Cancer Institute, Detroit, USA; ⁵Columbia University, New York, USA; ⁶Imperial College NHS Trust, London, United Kingdom

Prostate Cancer (PC) affects 1-in-8 men in the UK, and obesity 1-in-3. Termed an epidemic by WHO, obesity will shortly overtake smoking as the largest modifiable cancer risk-factor. High-fat diet is linked with increased risk of PC death, and volume of peri-prostatic adipose tissue (PPAT) is associated with increased PC lethality and reduced therapy-response. Furthermore, weight-gain/ central-obesity are major side-effects of mainstay androgen-deprivation therapy. Molecular mechanisms underpinning obesity-driven PC remain unknown. PPAT EVs from obese patients significantly increase proliferation, migration, epithelial-to-mesenchymal transition and invasion of PC cells. SNP analysis of RNA-seq data from PPAT EV-treated PC cells reveals EV phenotypic effects are not attributable to transferred long RNAs, but PPAT EVs contain distinct microRNA cargo compared to non-prostatic adipose (NPAT), with targets linked to Rho-GTPase signalling and cell-adhesion. PPAT EV proteomics identifies proteins involved in glycolysis, ATP-synthesis, and Rho-GTPase signalling, suggesting PPAT EVs may modulate metabolism and ECM-associations and metastasis in target PC cells. Consistently, RNA-seq of PPAT EV-treated PC cells revealed dysregulation of Rac/Rho, EGFR-signalling and cytoskeleton dynamics, with differential impacts in lean-versus-obese context. Top PPAT EV-dysregulated genes are increased in PC-versus-normal tissue, associate with reduced survival and significantly alter PC proliferation/migration. One such is TBX1, a developmental transcription-factor significantly elevated following treatment with PPAT-vs-NPAT EVs. TBX1 silencing significantly reduced PC cell proliferation/migration, but did not impact non-cancerous cells. Importantly, PPAT-enhanced TBX1 altered TGFB-mediated Rho-GTPase pathway-activation, leading to increased activity of Paxillin, a key regulator of focal adhesions (FAs) that promotes FA-turnover and motility. Indeed, TBX1 silencing increased PC cell ECM-adhesion and reduced expression of Rho-GTPase genes, whilst treatment with PPAT-vs-NPAT EVs increased this. We implicate Rho-GTPase signalling as a causal driver of PPAT-driven PC aggressivity through TBX1-mediated cell-adhesion changes, increasing PC motility/ migration. PPAT EV miR and protein cargo may be responsible for these phenomena.