Pancreatic Damage in Ovarian Cancer-Associated Cachexia Is Driven by Activin A Signalling

Area of Science:

• Oncology
• Metabolic Disorders
• Endocrinology

Background:

• Cancer-associated cachexia (CAC) is a metabolic disorder causing weight loss and tissue depletion, significantly impacting cancer patient mortality.
• The effects of CAC on the pancreas are not well understood, representing a gap in current medical knowledge.

Purpose of the Study:

• To investigate the impact of cancer-associated cachexia on pancreatic structure and function.
• To identify molecular mechanisms driving pancreatic damage during cachexia, focusing on the role of activin A.

Main Methods:

• Utilized a mouse model with PI3K activation in oocytes to induce cachexia and granulosa cell tumors (GCTs).
• Performed histological and molecular analyses of pancreatic tissue, including assessment of acinar cell size, zymogen granules, amylase activity, fibrosis, and cell death.
• Examined the effects of ovariectomy and Follistatin 288 (FST288), an activin A inhibitor, on cachexia and pancreatic pathology.

Main Results:

• Cachectic mice with GCTs showed significant pancreatic atrophy, reduced acinar cell size, and diminished amylase levels compared to controls.
• Pancreatic islets remained intact, but acinar cells exhibited fibrosis, cell death, and reduced function.
• Activin A signaling, via ACVR2B and p-SMAD3, was identified as a key driver of pancreatic acinar cell atrophy.
• Inhibition of activin A with FST288 rescued pancreatic atrophy without affecting tumor size.

Conclusions:

• Pancreatic damage is a significant feature of cancer-associated cachexia.
• Activin A is a critical mediator of pancreatic damage in CAC.
• Targeting activin A signaling presents a potential therapeutic strategy to preserve pancreatic function in cancer patients experiencing cachexia.