Oral Presentation The Pancreas Summit 2025

PICALM in Pancreatic Stellate Cell and Cancer Cell Coculture-Derived Exosomes – Mediator of Pancreatic Cancer-Related Diabetes? (126979)

Helen Binang 1 2 , Rohit Sarkar 1 2 , Wilson Wong 3 , Anand Hardikar 3 , S. M. Zahid Hosen 1 2 , Zhihong Xu 1 2 , Parvathy Rajan 1 2 , Ron Pirola 1 2 , Jeremy Wilson 1 2 , Chamini Perera 1 2 , Minoti Apte 1 2
  1. Pancreatic Research Group, South Western Sydney Clinical Campuses, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, NSW, Australia
  2. Ingham Institute for Applied Medical Research, Sydney 2170, NSW, Australia
  3. Western Sydney University, Sydney, NSW, Australia

Background: Pancreatic cancer-related diabetes (PCRD) may be a harbinger of PC. Pancreatic stellate cells (PSCs) produce PC stroma and interact with cancer cells promoting cancer progression. These interactions may also promote PCRD via secretions carried in exosomes that impair islet cell function and peripheral insulin signalling. We have previously shown that i) compared to acinar exosomes (controls), mouse PSCs + cancer cell (KPC) coculture-exosomes (P+K-ex) significantly decrease expression of insulin signalling factors (insulin receptor (IR) and glucose transporter 2 (GLUT2)) in mouse hepatocytes. ii) mRNA levels of phosphatidylinositol binding clathrin assembly protein (PICALM, associated with impaired glucose tolerance and poor survival in PC) is upregulated in P+K-ex, and in plasma of glucose intolerant PC bearing mice suggesting that PICALM may mediate PCRD. 

Aim: To examine the role of exosomal PICALM in regulation of insulin signalling by mouse hepatocytes.

Methods: Mouse PSCs and KPC cells were transfected with PICALM siRNA (si-PICALM) or scramble siRNA (Scr ctrl), and then cocultured in Boyden chambers (n=3/group). Exosomes were isolated (P+K-ex) by ultracentrifugation. Mouse hepatocytes (AML12) were incubated with si-PICALM and Scr ctrl exosomes for 24 hours; IR and GLUT2 expression were assessed in AML12 cell lysates by immunoblotting.

Results: Compared to exosomes from Scr ctrl treated PSCs and KPCs, PICALM mRNA levels in exosomes from si-PICALM treated PSCs and KPC were significantly decreased confirming efficacy of siRNA treatment (p < 0.0001). PICALM inhibited exosomes ii) caused a significant increase in the expression of IR, abrogating the effect of P+K-ex and restored GLUT2 expression, overturning the P+K-ex induced reduction in GLUT2 expression in hepatocytes.

Conclusion: PICALM-inhibited exosomes caused a significant increase in the expression of IR, and restored GLUT2 expression, overturning the P+K-ex induced reduction in IR and GLUT2 expressions in hepatocytes.

Implication: Exosomal PICALM from PSC-PC interactions may mediate diabetogenic effects and thus play a role in PCRD, making it a potential novel biomarker/therapeutic target in PC.