Role of Activin Signaling in Pancreatic Cancer Progression

Pancreatic ductal adenocarcinoma (PDAC) is the fourth -leading cause of cancer-related death with a 5-year survival as low as 9%. Lethality remains high due to increased metastatic potential and reduced patient condition due to cachexia that prevents them from withstanding aggressive chemotherapy drugs. Novel therapeutic and prognostic targets for PDAC are urgently needed to improve patient survival. One unappreciated candidate is activin, a member of the TGF family. In PDAC patients, serum activin levels have been shown to be significantly higher and associated with cancer cell stemness and cachexia. Hence, we focused our efforts on activin ligand and activin receptor type 1a (ACVR1a) to examine the factors that render activin signaling as a promoter of PDAC progression. Here, we conducted in vitro and in vivo experiments to expose PDAC cells to activin A and determine its impact on disease potential by measuring cell growth, migration and metastasis. We also manipulated the expression of ACVR1a in the murine pancreas of an established pancreatic cancer mouse model and measured the progression of disease compared to control mice. Our studies show that activin A expression in the stromal fraction of human pancreatic tissue correlates to worse prognosis. Pancreatic stromal cells secrete high levels of activin A that increases epithelial cancer cells metastatic potential. Inhibition of activin A in vivo with a activin A specific neutralizing antibody reduced metastasis formation and cancer-induced cachexia. Meanwhile, in vivo manipulation of ACVR1a showed a significant survival benefit in mice without receptor expression but a constitutively active receptor in the pancreas was sufficient to drive accelerated invasive PDAC disease compared to control mice. This work defines activin signaling in late stages of PDAC as an important contributor to metastasis and advancement of disease. The delay on disease progression upon inhibition of activin A and ACVR1a separately, provide evidence that these novel therapeutic targets can be translated into the clinic. Patients that present with high levels of circulating activin A could benefit from activin A inhibition. In cases where a tissue biopsy can be collected, activin A and ACVR1a immunostaining could also stratify patients who can benefit from inhibition to both activin ligand and receptor combination therapy.