Figure 1.

Interplay of signaling pathways: cellular dynamics within the pancreatic ductal adenocarcinoma microenvironment. The activation of SCs from a quiescent to an active state is induced by IL6 release from cancer cells. The hypoxic tumor state upregulates GM-CSF, promoting the migration and proliferation of SCs. Reciprocal paracrine signaling is established between cancer cells and SCs, with cancer cells releasing TIMP1 and NGF to influence SCs. Conversely, SCs release TGF-b and L1CAM, impacting cancer cells and contributing to NI. SCs play a multifaceted role by recruiting macrophages through the release of IL33 and CCL2. The CCL2-CCR2 pathway prompts TAMs to emit cathepsin B, thereby promoting nerve injury. TAMs, activated by IL33, release bFGF, establishing a positive feedback loop within the microenvironment. This intricate interplay highlights the dynamic and interconnected nature of cellular communication in the context of PDAC. Abbreviations: SCs, Schwann cells; GM-CSF, granulocyte–macrophage colony-stimulating factor; TIMP1, tissue inhibitor of metalloproteinases 1; NGF, nerve growth factor; TGF-b, transforming growth factor-beta; L1CAM, L1 cell adhesion molecule; NI, neural invasion; CCL2, chemokine ligand 2; TAMs, tumor-associated macrophages; bFGF, basic fibroblast growth factor; and PDAC, pancreatic ductal adenocarcinoma.