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

Cancer Research · 2026-04-03

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.

Abstract 5000: Activin receptor subtype-2A regulates innate immune cell activation and non-canonical signaling in pancreatic cancer cells

Cancer Research · 2026-04-03

Abstract More than 50% of all pancreatic cancer patients present with distant metastasis at the time of diagnosis highlighting the need for early biomarkers of pancreatic cancer progression. Inflammatory disorders of the pancreas increases the risk for developing pancreatic cancer suggesting an inflammatory component to disease initiation. Our research team has previously shown that activin A (activin), a critical inflammatory cytokine, contributes to pancreatitis development through activation of innate immune cells. Furthermore, activin co-localizes with pancreatic intraepithelial neoplasm (PanIN) lesions in a mouse model of inflammation assisted pancreatic ductal adenocarcinoma (PDAC). Here, we will test the hypothesis that activin is an early, targetable biomarker of PDAC. Western blots were performed to quantify pSMAD2/3, pERK, and PI3K on pancreatic cancer cells stimulated with activin in the presence/absence of anti-activin neutralizing antibody or a highly specific activin receptor subtype-2A (ACVR2A) inhibitor. qPCR was performed to quantify chemokine receptor expression in RAW264.7 macrophages and neutrophil-like HL-60 cells exposed to the same conditions. Transwell migration assays were performed on RAW264.6 macrophages exposed to conditioned media from pancreatic stellate cells treated with activin in the presence/absence of anti-activin neutralizing antibody or the ACVR2A inhibitor. Prelimindary data suggests ACVR2A regulates SMAD2/3 phosphorylation in pancreatic cancer cells. We also observed ACVR2A dependent increases in the migratory capacity of macrophages that was regulated via activin. Taken together, these data suggest activin mediates PDAC initiation and progression via activin-mediated ACVR2A signaling. Citation Format: Yuchen Wang, Mark B. Wiley, Jessica Bauer, Xinru Wang, Jordi Guillem-Marti, David Lee, David Baker, Barbara Jung. Activin receptor subtype-2A regulates innate immune cell activation and non-canonical signaling in pancreatic cancer cells [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 5000.

Progression of cirrhosis and the IL-23/IL-17 axis: cytokine profiling from stable disease to ACLF

Zeitschrift für Gastroenterologie · 2025-09-01

Tu1411: ACTIVIN A IS ASSOCIATED WITH A REDUCTION IN STROMAL ACTIVITY, MEMORY T-CELL AND MACROPHAGE RECRUITMENT IN PDAC

Gastroenterology · 2025-05-01

Activin A affects colorectal cancer progression and immunomodulation in a stage dependent manner

Scientific Reports · 2025-03-12 · 3 citations

Advanced colorectal cancer (CRC) continues to present with poor survival and treatment options remain limited. We have shown that increased activin A (activin) expression in the tumor microenvironment (TME) is associated with poor outcome in a cohort of stage III and IV CRC patients. Here, we hypothesized that activin promotes stage specific outcomes in CRC, enhancing metastasis and tolerance in late-stage CRC exclusively. We employed Digital Spatial Profiling (DSP) technology on a cohort of stage II and III CRC patient tissue samples obtained at the time of curative surgery to show that activin co-localization was associated with increased mitogenic signaling, proliferation, and immunosuppression in stage III, but not stage II, CRCs. Furthermore, we found strong linear correlations between markers of immunosuppression and signaling proteins in activin (+) areas, an effect that was not observed in activin (-) areas of tissue. Taken together these data suggest activin exerts pro-metastatic and immunosuppressive effects in stage III, but not stage II, CRC providing an attractive therapeutic target for advanced CRC.

Su1444 ACTIVIN A SIGNALING STIMULATES INNATE IMMUNE CELL ACTIVATION IN PANCREATITIS

Gastroenterology · 2024-05-01

Transfiguration of Academic Departments of Medicine

The American Journal of Medicine · 2024-09-19

Activin A signaling stimulates neutrophil activation and macrophage migration in pancreatitis

Scientific Reports · 2024-04-23 · 3 citations

Abstract Acute Pancreatitis (AP) is associated with high mortality and current treatment options are limited to supportive care. We found that blockade of activin A (activin) in mice improves outcomes in two murine models of AP. To test the hypothesis that activin is produced early in response to pancreatitis and is maintained throughout disease progression to stimulate immune cells, we first performed digital spatial profiling (DSP) of human chronic pancreatitis (CP) patient tissue. Then, transwell migration assays using RAW264.7 mouse macrophages and qPCR analysis of “neutrophil-like” HL-60 cells were used for functional correlation. Immunofluorescence and western blots on cerulein-induced pancreatitis samples from pancreatic acinar cell-specific Kras knock-in ( Ptf1aCre ER ™; LSL-Kras G12D ) and functional WT Ptf1aCre ER ™ mouse lines mimicking AP and CP to allow for in vivo confirmation. Our data suggest activin promotes neutrophil and macrophage activation both in situ and in vitro, while pancreatic activin production is increased as early as 1 h in response to pancreatitis and is maintained throughout CP in vivo. Taken together, activin is produced early in response to pancreatitis and is maintained throughout disease progression to promote neutrophil and macrophage activation.

The Role of TGF-Beta in Cancer

Elsevier eBooks · 2024-01-01

Acute Pancreatitis

Pancreas · 2023-07-01 · 25 citations

OBJECTIVE: Severe acute pancreatitis (SAP), pancreatic inflammation leading to multiorgan failure, is associated with high morbidity and mortality. There is a critical need to identify novel therapeutic strategies to improve clinical outcomes for SAP patients. MATERIALS AND METHODS: A comprehensive literature review was performed to identify current clinical strategies, known molecular pathophysiology, and potential therapeutic targets for SAP. RESULTS: Current clinical approaches focus on determining which patients will likely develop SAP. However, therapeutic options are limited to supportive care and fluid resuscitation. The application of a novel 5-cytokine panel accurately predicting disease outcomes in SAP suggests that molecular approaches will improve impact of future clinical trials in AP. CONCLUSIONS: Inflammatory outcomes in acute pancreatitis are driven by several unique molecular signals, which compound to promote both local and systemic inflammation. The identification of master cytokine regulators is critical to developing therapeutics, which reduce inflammation through several mechanisms.