Abstract 5104: Fibrosis activates pancreatic cancer Schwann cells in a non-canonical pathway through a nuclear mechanosensing mechanism

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with only 12% of patients surviving 5 years after diagnosis. Several elements of the PDAC tumor microenvironment (TME) including fibrosis and tumor innervation contributes to the malignancy, but how they affect each other is unstudied. Here we report a relationship between the stiff desmoplastic environment of PDAC and Schwann cell (SC) activation in nerves of the tumor. The activated SCs reprogram into cells that induce cancer cell spread via activation of the transcription factor c-Jun and the formation of tracks for cancer cells. We show how mechanical forces encountered by SCs in the stiff TME activate SC in a non-canonical manner. We use in vivo and in vitro live imaging, mechanobiology and computational analysis of transcriptomic data, as well as several models including human PDAC specimens, mouse models of pancreatic fibrosis and cells expressing live reporter for c-Jun phosphorylation. We report a positive correlation between c-Jun phosphorylation in SCs of nerves and stiffness of the stroma surrounding these nerves, suggesting a role for stromal stiffness in SC activation. To monitor c-Jun phosphorylation in live SCs, we express a c-Jun kinase translocation reporter (KTR), a fluorescent biosensor that translocates from the nucleus to the cytoplasm upon phosphorylation of a c-Jun motif, in the cell line HEI-286 SCs. Imaging of HEI-286 KTR SCs injected in murine fibrotic and non-fibrotic pancreas shows an association of activated cells with fibrosis. Intravital 4D multiphoton microscopy allows the observation of HEI-286 KTR SCs along collagen fibers and shows a concomitant change of nuclear shape with KTR translocation. Using three different in vitro models, we show that mechanical forces on HEI-286 KTR SCs induce KTR translocation. We show that this activation is associated with a cPLA2 activity and an increase of the AP1 transcription factor network molecules, but not with the expression of the conventional Jun kinase molecules. The results support a nuclear mechanical sensing mechanism inducing SC activation in PDAC through a non-canonical mechanism of c-Jun activation. Furthermore, we show that the SC cellular stress response differs from the cancer cell response. We propose that SCs is activated by two different mechanisms localized at the nucleus and at the plasma membrane. The findings reveal therapeutic opportunities to treat PDAC by indirect targeting of specific component of the TME. Citation Format: Pavel Stupakov, Golbahar Sadatrezaei, Ines Velazquez Quesada, Lillian Boe, Efsevia Vakiani, Bojana Gligorijevic, Boris Reva, Richard J. Wong, Sylvie Deborde. Fibrosis activates pancreatic cancer Schwann cells in a non-canonical pathway through a nuclear mechanosensing mechanism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5104.