Abstract A016: Aspirin Reprograms Pancreatic Stellate Cells to Suppress Tumor– Nerve Interaction in Pancreatic Cancer
Sıla Sığırlı, Gizem Selimoğlu, Didem Karakaş, Engin Ulukaya, İhsan Ekin Demir, Güralp Onur CeyhanAbstract
Introduction:
Neural invasion (NI) is a major contributor to poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Pancreatic stellate cells (PSCs), the dominant stromal population, enhance tumor aggressiveness and active even in pre-neoplastic pancreatic intraepithelial neoplasia (PanIN) lesions. Schwann cells guide cancer cell migration along nerves and are also found near PanINs, indicating that tumor–nerve-fibroblast crosstalk arises early in carcinogenesis. Yet, how PSCs regulate the communication between PDAC cells and SCs remains poorly understood. Aspirin (ASA), an anti-inflammatory agent, may modulate the tumor stroma beyond its pharmacologic actions. We investigated whether ASA reprograms PSCs to limit their ability to promote PDAC–Schwann interactions to mitigate neural invasion.
Methods:
PSCs were treated with non-cytotoxic doses of ASA (2.5 mM). Conditioned media (CM) were collected from untreated (NT PSC) and ASA-treated PSCs (ASA PSC). PANC-1, T3M4 cells and SCs were exposed to these CMs, and their functional behaviors were compared. qPCR and Western blot were used to assess epithelial–mesenchymal transition (EMT) markers in PDAC cells and dedifferentiation markers (GFAP, S100) in Schwann cells exposed to NT or ASA PSC media. Additionally, 3D migration model used to quantify the reciprocal migration between cancer-Schwann cell and cancer-DRG neurons under NT or ASA PSC CM. Organotypic tissue slices from KC and KPC mice used to understand PSC activation under ASA treatement. LC/MS analysis used to identify key changes in PSC secretome after ASA treatment.
Results:
Conditioned media from untreated PSCs strongly enhanced PDAC and Schwann cell migration and invasion, reflecting a robust PSC-driven pro-invasive phenotype. In contrast, ASA-treated PSC-CM significantly diminished these effects, suggesting a functional reprogramming of PSCs toward a tumor-restraining state. In 3D co-cultures, the untreated PSC secretome promoted dynamic, bidirectional PDAC–Schwann/DRG neurons migration, which was almost completely reversed by ASA exposure. Furthermore, OTCs showed that ASA treatment reshaped PSC distribution within the tumor, indicating stromal remodeling consistent with ASA-induced reprogramming of the PSC in tumor microenvironment.
Conclusion:
The results demonstrate that aspirin attenuates PSC-mediated signaling involved in tumor–nerve crosstalk in PDAC. By reprogramming PSCs, ASA diminishes Schwann activation and PDAC neurotropism, highlighting stromal modulation as a feasible strategy to limit neural invasion.
Citation Format:
Sıla Sığırlı, Gizem Selimoğlu, Didem Karakaş, Engin Ulukaya, İhsan Ekin Demir, Güralp Onur Ceyhan. Aspirin Reprograms Pancreatic Stellate Cells to Suppress Tumor– Nerve Interaction in Pancreatic Cancer [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A016.