Abstract 4992: Activin A promotes PDAC progression via immunosuppression and non-canonical signaling

Abstract The five-year survival rate for pancreatic cancer patients remains at 13%. More than 90% of these patients are diagnosed with pancreatic ductal adenocarcinoma (PDAC). Acute pancreatitis and chronic pancreatitis are risk factors for developing PDAC suggesting a strong inflammatory role for disease initiation. Recently, we found that activin a (activin), a TGFβ superfamily member, drives inflammation in acute pancreatitis via recruitment of macrophages and activation of neutrophils. In keeping with this, we recently showed that PDAC patients with high activin expression in the stroma have a worse prognosis and that inhibition of activin in mice decreased metastasis suggesting PDAC patients might benefit from activin inhibition. Here, we expand our studies in PDAC in the setting of inflammation and activin signaling. Digital Spatial Profiling (DSP) was performed on a tissue microarray of PDAC patients which permitted visualization and separation of images based on PanCK and activin localization. Tumor and stroma compartments were separated via PanCK expression and the quantification of 56 proteins was performed in activin (+) and (-) areas within each compartment. Western blots were employed to quantify the phosphorylation of p38 and SMAD2/3 in MIA PaCa-2, and AsPC-1 pancreatic cancer cell lines treated with/out activin. DSP data revealed activin (+) areas in the tumoral compartment had reduced total immune, total T cell, T helper, and memory T cell infiltrations when compared to activin (-) areas. This effect was coupled to increased markers of the MAPK and PI3K pathways in activin (+) areas. In vitro, activin stimulated phosphorylation of p-38, p-90, and SMAD2/3 in primary pancreatic cancer cells, but not in metastatic pancreatic cancer cells suggesting that activin may mediate stage-specific outcomes. Taken together, these data suggest that activin is a targetable molecule promoting a cancer supportive microenvironment in PDAC. Citation Format: Mark B. Wiley, Jessica Bauer, Yuchen Wang, Barbara Jung, . Activin A promotes PDAC progression via immunosuppression and non-canonical signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4992.