Visceral adipose tissue remodeling in pancreatic ductal adenocarcinoma cachexia: the role of activin A signaling

Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer death in the United States and is projected to become the second leading cause by the year 2030. Prognosis for patients with metastatic disease remains dismal, with cachexia as a main contributor to the low survival rate. Emerging reports indicate that PDAC patients display distinct phenotypes of cachexia development, with either adipose tissue loss preceding skeletal muscle wasting or loss of only adipose tissue. While muscle wasting has been the most frequently studied mechanism in cachexia research, changes in adipose tissue are increasingly understood as important components of body weight loss in cachectic patients. We hypothesized that there is a correlation between the marked increase in production of activin A, a previously proposed biomarker of cancer cachexia, in PDAC patients and the remodeling of adipose tissue and consequent cancer-associated cachectic state. We measured serum activin A levels of a cohort of Stage IV PDAC patients and analyzed the expression of activin A in tumor-derived cell lines and tumor samples of both humans and a genetically engineered mouse model. We further investigated the effect of activin A on remodeling of adipose tissue secondary to tumor progression in omental adipose tissue of Stage IV PDAC patients and the gonadal fat pad of an orthotopic mouse model of PDAC. Our data revealed that serum activin A levels were significantly elevated in Stage IV PDAC patients in comparison to age-matched non-cancer patients. We established a correlation between elevated activin A and remodeling of visceral adipose tissue. Atrophy and fibrosis of visceral adipose tissue was examined in omental adipose tissue of Stage IV PDAC patients and gonadal adipose tissue of an orthotopic mouse model of PDAC. Remarkably, white visceral adipose tissue from both PDAC patients and mice exhibited decreased adipocyte diameter and increased fibrotic deposition. Strikingly, expression of thermogenic marker UCP1 in visceral adipose tissues of PDAC patients and mice remained unchanged. Collectively, our data revealed a novel role of activin A in cachectic visceral adipose tissue loss and remodeling during the progression of PDAC