Oncogene-induced senescence limits the progression of pancreatic neoplasia through production of Activin A.

Pancreatic ductal adenocarcinoma (PDA) is a deadly and aggressive cancer. Understanding mechanisms that drive pre-neoplastic pancreatic lesions is necessary to improve early diagnostic and therapeutic strategies. Mutations and inactivation of activin-like kinase (ALK4) have been demonstrated to favor PDA onset. Surprisingly, little is known regarding the ligands that drive ALK4 signaling in pancreatic cancer or how this signaling pathway limits the initiation of neoplastic lesions. In this study, data mining and histological analyses performed on human and mouse tumor tissues reveal that Activin A is the major ALK4-ligand that drives PDA initiation. Activin A, which is absent in normal acinar-cells, was strongly induced during acinar-to-duct metaplasia (ADM), which was promoted by pancreatitis or the activation of KrasG12D in mice. Activin A expression during ADM was associated with the cellular senescence program that was induced in precursor lesions. Blocking Activin A-signaling through the use of a soluble form of Activin receptor IIB (sActRIIB-Fc) and ALK4-knockout (KO) in mice expressing KrasG12D resulted in reduced senescence associated with decreased expression of p21, reduced phosphorylation of H2A histone family member X (H2AX), and increased proliferation. Thus, this study indicates that Activin A acts as a protective senescence-associated secretory phenotype (SASP) factor produced by Kras-induced senescent cells during ADM, which limits the expansion and proliferation of pancreatic neoplastic lesions.