Abstract 2355: Transcription factor EB modulates fibrotic response in pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC), which comprises 85% of all the pancreatic cancers, is one of the most aggressive and deadly tumor that exists today with less than 8% of survival 5 years after diagnosis. It is predicted to become the second cause of cancer death by 2030. A typical characteristic of this tumor is the presence of prominent stroma component mainly produced by Pancreatic Stellate Cells (PSCs) in response to soluble factors released by cancer cells. PSCs activation and differentiation into CAF (Cancer-associated fibroblasts) is a reversible process, which impacts on both tumor progression and drug resistance. Transcription factor EB (TFEB) is mostly known as a master regulator of autophagy and lysosomal biogenesis. A recent study demonstrated that TFEB inhibits epithelial-to-mesenchymal transition (EMT) and myofibroblast differentiation in epicardial cells by upregulating TGIF1, a TGFβ pathway repressor. Based on this observation, we investigated if TFEB might have an inhibitory role in PSCs activation, taking into consideration the crucial role of TGFβ signaling in this process. The TFEB expression, measured by immunostaining, was significantly downregulated in CAFs in human PDAC samples compared to PSCs in healthy pancreas. In PSCs, co-cultured with PDAC cell lines, CAF markers were upregulated while TFEB expression was downregulated. The overexpression of TFEB in PSCs suppressed CAF markers upregulation induced by co-culture with PDAC cells at both mRNA and protein levels. The bulk RNAseq analysis showed the differential expression of genes required for extracellular matrix production, fibrotic response and inflammation in PSCs co-cultured with PDAC cell lines versus PSCs alone, with and without TFEB overexpression. These in vitro data suggest a role for TFEB in PSCs activation and stroma formation which will be further investigated in PDAC mouse models. Citation Format: Alejandra Diaz Alcalde, Edoardo Vallariello, Elena Astanina, Emanuele Middonti, Federico Bussolino. Transcription factor EB modulates fibrotic response in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2355.