Mechanism of cancer-associated fibroblasts-derived exosomes-shuttled snail regulating the SOCS6/HIF-1α axis to promote pancreatic cancer stemness and gemcitabine resistance.

Cancer-associated fibroblasts (CAFs) contribute to pancreatic cancer (PC) progression and therapeutic resistance. This study investigated whether CAF-derived exosomes (CAF-exo)-promote PC cell stemness and gemcitabine (GEM) resistance by delivering Snail and regulating the suppressor of cytokine signaling 6/hypoxia-inducible factor-1α (SOCS6/HIF-1α) axis. Tumors and paired adjacent tissues from patients with PC were collected. RT-qPCR measured Snail, SOCS6, and HIF-1α mRNA; correlations were assessed by Pearson analysis, and survival by Kaplan-Meier. CAFs and normal fibroblasts were isolated for Exo extraction. PC cells (SW1990/MiaPACa2) were treated with lentiviral sh-Snail-transfected CAF-exo, oe-Snail, oe-SOCS6, or si-HIF-1α. Nanog, octamer-binding transcription factor 4 (OCT4), SRY-box transcription factor 2 (SOX2), Snail, SOCS6, and HIF-1α, as well as spheroid formation, chemoresistance, viability, and apoptosis, were evaluated. Snail's binding to the SOCS6 promoter was confirmed by dual-luciferase and ChIP-qPCR. A xenograft mouse model was established for in vivo validation. In PC tissues, Snail and HIF-1α were elevated, SOCS6 reduced; Snail negatively correlated with SOCS6 and positively with HIF-1α, and these patterns were associated with poor survival. CAF-exo delivered Snail into PC cells, elevating stemness markers, sphere formation, and GEM resistance, which were reversed by Snail knockdown. Mechanistically, CAF-exo transcriptionally represses SOCS6 via Snail, leading to HIF-1α upregulation. SOCS6 upregulation or HIF-1α knockdown partly attenuated CAF-exo-induced stemness and GEM resistance. In vivo, CAF-exo promoted tumor growth, stemness, and GEM resistance and reduced apoptosis via the Snail-SOCS6/HIF-1α axis. CAF-exo shuttled Snail, transcriptionally suppressed SOCS6 expression to activate HIF-1α, thereby enhancing PC cell stemness and GEM resistance in PC cells.