Abstract
Background:
Cancer-associated cachexia (CAC) is a severe metabolic disorder characterized by involuntary weight loss, skeletal muscle atrophy and adipose tissue depletion. It is a major contributor to morbidity and mortality in the advanced stages of various cancers. However, the impact of CAC on the pancreas remains largely unexplored.
Methods:
We used mice with constitutively active PI3K in oocytes, generated through a Cre-inducible Pik3ca* knock-in allele driven by Gdf9-icre and performed histological and molecular analyses of the pancreas during cachexia development. Additionally, we examined pancreatic changes following ovariectomy and administration of Follistatin 288 (FST288).
Results:
Mice that developed cachexia symptoms associated with granulosa cell tumour (GCT) growth exhibited significant pancreatic atrophy compared to controls (Cre+ vs. Cre- at PD83, p < 0.0001), including reduced size of individual acinar cells (102.99 ± 12.19 μm2 vs. 207.94 ± 24.85 μm2 at PD83, p < 0.0001) and acinar units (346.41 ± 169.22 μm2 vs. 1193.59 ± 136.01 μm2 at PD83, p < 0.0001), despite comparable food intake between groups. Acinar cells exhibited a decrease in zymogen granules, reduced amylase expression and diminished amylase activity in both serum (0.29 ± 0.08 vs. 1.41 ± 0.40, p < 0.001) and tissue (0.37 ± 0.14 vs. 1.05 ± 0.29, p < 0.01). In contrast, pancreatic islets remained intact, as evidenced by histological analysis and preserved insulin expression. The pancreas of PD83 Cre+ mice also developed fibrosis and acinar cell death, characterized by elevated expression of collagen IV and α-SMA, and TUNEL-positive signals in acinar cells, respectively. Ovariectomy preserved body weight (2.66 ± 1.30 g for Cre+/OVX vs. 1.60 ± 0.97 g for Cre-) compared to Cre+ mice (-3.66 g) and maintained pancreatic function, suggesting that tumour-derived factors from GCT contribute to the severity of cachexia. Acinar cells showed high expression of ACVR2B, leading to activation of downstream p-SMAD3 signalling. Accordingly, activin A directly induced acinar cell atrophy in both ex vivo cultured pancreas (79.27 ± 19.03 μm2 vs. 171.14 ± 27.01 μm2, p < 0.0001) and 266-6 acinar cells, as evidenced by reduced acinar cell size and decreased amylase production. Injection of FST288, an activin A inhibitor, rescued pancreatic acinar atrophy (252.95 ± 11.59 μm2 in Cre+/FST288 vs. 97.25 ± 12.37 μm2 in Cre+, p < 0.001) without affecting GCT tumour size. Ex vivo culture of pancreas and 266-6 acinar cells exposed to activin A confirmed that activin A directly induces pancreatic damage.
Conclusions:
These findings demonstrate pancreatic damage occurs during CAC development and highlight the critical role of activin A in this process. Targeting activin A signalling may represent a promising therapeutic strategy to mitigate cachexia in cancer patients and preserve pancreatic function.
Keywords:
acinar cell atrophy; activin A; amylase; cachexia; follistatin 288.