Pancreatic cancer cell and stellate cell-derived exosome crosstalk mediates pancreatic cancer-related diabetes.

BACKGROUND

Diabetes is a known risk factor, and a distinct form termed pancreatic cancer-related diabetes (PCRD) often precedes the diagnosis of cancer by 3-5 years, offering a potential window for intervention. We hypothesised that interactions between stromal pancreatic stellate cells (PSCs) and cancer cells trigger secretion of exosomal factors that impair islet function and insulin signalling, contributing to PCRD pathogenesis.

METHODS

KC (KrasLSL-G12D/+; Pdx1-Cre) mice were fed a high-fructose diet (HFrD) or control diet for 16 weeks. Exosomes were isolated from monocultures and co-cultures of cancer/PanIN cells with PSCs, characterised by nanoparticle tracking analysis and transmission electron microscopy, and incubated with mouse β-cells (MIN6) and peripheral cells (hepatocytes, adipocytes, skeletal myocytes). Effects on insulin secretion and insulin-signalling factors were examined. Exosomal glucose-6-phosphate dehydrogenase (G6PD) expression was modulated by siRNA to assess functional impact.

RESULTS

HFrD induced marked glucose intolerance in KC mice and was accompanied by enhanced PSC activation, macrophage infiltration, inflammation, and accelerated PanIN progression. Exosomes from PSCs, cancer cells, and co-cultures displayed typical morphology and marker expression and were efficiently internalised by β-cells and hepatocytes. Functionally, exosomes significantly impaired glucose-stimulated insulin secretion in mouse and human β-cells without altering insulin content. In hepatocytes, PSC-, cancer-, and co-culture-derived exosomes reduced key insulin-signalling components, including IR, IRS, AKT, FOXO1 and GLUT2, and inhibited glucose uptake. Silencing exosomal G6PD partially restored hepatocyte insulin signalling.

CONCLUSION

This study identifies a potential contributor to PCRD and suggests a possible mechanistic role for exosomal G6PD in impaired insulin signalling associated with PCRD.