The impact of intrapancreatic glia cell depletion on tumor progression and pain in pancreatic cancer

• Applicants: Professor Dr. Ihsan Ekin Demir; Dr. Mara R. Goetz
• Subject Area: General and Visceral Surgery ; Gastroenterology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 445708649

Neural invasion (NI) is an independent prognostic factor in pancreatic ductal adenocarcinoma (PDAC). In our preliminary work, Schwann cells (SCs) were identified as interaction partners of PDAC cells and thus as carcinotropic cells and as initiators of NI in gastrointestinal tumors. Due to this very early and pronounced glial activation and glial-tumor interaction in PDAC, the question arises as to what role peripheral glial cells play in the development and progression of PDAC. The data now available from the initial application demonstrated that the activated SCs are highly relevant for PDAC progression, PDAC associated survival and for increased pain sensitivity. This is accompanied by SC-associated neuropathy, angiopathy and SC-associated immune cell infiltration in the tumor lesion and in the tumor precursors. The mechanism of how and via which transmitters Schwann and tumor cells interact remains unclear, and is therefore now the aim of this follow-up application. The proposed work program investigates the signaling pathways that mediate tumor cell-SC interaction in PDAC and the importance of inhibiting these signaling pathways for tumor development and associated neuropathy. Our hypothesis is that confrontation of tumor cells with human SCs activates very specific tumorigenic signaling pathways in these two cell types. In particular, this interaction leads to an upregulation of the expression of IL-6 and Col1A2 in the tumor cells, and of the chemokines CXCL2, CXCL3 and CXCL8 in the SCs, which are associated with the IL-17 signaling cascade. In this follow-up application, these signaling pathways will be investigated in more detail, confirmed and functionally validated in vivo based on our previous results.

• DFG Programme: Research Grants