Abstract
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. Exosomes as carriers of miRNAs in blood encode the metabolic status of the originating tissues and deliver their cargo to target tissues. We hypothesized that T2D plasma exosomes induce epithelial-mesenchymal transition (EMT) and immune checkpoints in prostate cancer cells. Here, we show that plasma exosomes from subjects with T2D induce EMT features in prostate cancer cells and upregulate the checkpoint genes CD274 and CD155. We prove that specific exosomal miRNAs abundant in T2D plasma (miR374a-5p, miR-93-5p, miR-424-5p) are delivered to tumor cells and regulate these 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 drive EMT and immune ligand expression through BRD4. The results suggest novel, non-invasive approaches to evaluate prostate cancer progression risk in patients with comorbid T2D.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Grant support: This study was supported by grants from the National Institutes of Health (DK090455, U01CA182898, R01CA222170; GV Denis).
Abbreviations
- ADT
- androgen deprivation therapy
- BET
- Bromodomain and ExtraTerminal
- DAPI
- 4’,6-diamidino-2-phenylindole dihydrochloride
- EMT
- epithelial-to-mesenchymal transition
- FBS
- fetal bovine serum
- FDR
- false discovery rate
- IFN
- interferon
- IPA
- Ingenuity Pathway Analysis
- ND
- non-diabetic
- PCA
- principal components analysis
- PD-L1
- programmed death-ligand 1
- PROTAC
- proteolysis-targeting chimera
- PSA
- prostate specific antigen
- T2D
- Type 2 diabetes
- TGF
- Transforming Growth Factor
- VST
- variance-stabilizing transformation