Pancreatic Ductal Adenocarcinoma Highly Expresses Activin A: Implications in Adipose Tissue and Cancer Cachexia

Abstract

Background: 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. Cancer cachexia is seen in over 85% of PDAC patients who often have the most severe degrees of cachexia and experience adipose tissue loss prior to skeletal muscle loss early in the disease process. Several factors have been proposed to induce cachectic symptoms in human patients, including inhibin subunit βA, or activin A. Hypothesis: 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 activin A production in PDAC patients and the remodeling of adipose tissue and consequent cancer-associated cachectic state. Experimental Design: We measured serum activin A levels of a cohort of PDAC patients and analyzed the expression of activin A in tumor-derived cell lines and biopsies of both humans and mice. We further investigated the effect of activin A on remodeling of adipose tissue secondary to tumor progression in PDAC patients and an orthotopic murine model. Results: We observed that PDAC cell lines express and secrete activin A. We recognized a loss of adipose tissue mass and adipocyte diameter in PDAC patients and our orthotopic PDAC mouse model in relation to increased circulating activin A. We also noted that both exogenous activin A and conditioned medium from pancreatic tumor-derived cell lines dampened adipocyte differentiation and lipid droplet formation via reduction of PPARγ expression in mouse mesenchymal stem cells. These treatment conditions also reduced lipid droplet size without upregulating traditional markers of adipose tissue browning and lipolysis such as UCP-1 and ATGL in mature mouse adipocytes. PPARγ, UCP-1, and ATGL expression are also heavily downregulated in adipose tissue of PDAC patients. Furthermore, our studies revealed that the expression of extracellular matrix proteins such as collagen I and fibronectin is dramatically upregulated in adipose tissue of PDAC patients and our orthotopic PDAC mouse model. Thus, we found that there is a clear correlation between elevated levels of activin A and the progression of cancer-associated cachexia in PDAC. Discussion: Our results reveal an imperative role of activin A in relation to the loss and remodeling of adipose tissue in the progression of cachexia in PDAC patients.