Figure 2.

Contribution of extracellular matrix (ECM)/fibrosis to pancreatic ductal adenocarcinoma (PDAC) pathogenesis. Activated pancreatic stellate cells (aPSC) release significant quantities of ECM components, including collagen, periostin, fibronectin, and matrix metalloproteinases (MMPs) into the PDAC tumor microenvironment (TME) that contribute to fibrosis. The fibrotic PDAC TME results in several pathogenic effects (noted in red text). The abundance of fibrotic material in the PDAC TME can result in hypoxia and decreased tumor perfusion, which inhibit the therapeutic effects of radiotherapy and chemotherapy, respectively. Moreover, fibrosis can lead to hypoglycemia and nutrient deprivation in the TME. In response to nutrient deprivation, PDAC tumor cells metabolically adapt by stimulating autophagy in aPSCs, leading to release of alanine from aPSCs, which is then used for fuel by the PDAC tumor cells. The aPSCs may also stimulate autophagy in PDAC tumor cells. Immunosuppression in the TME is established in part by the release of galectin-1 and CXCL12 by aPSCs, inhibiting CD3⁺ T cells and sequestering CD8⁺ T cells, respectively. Additionally, release of interleukin-6 (IL-6) by aPSCs results in conversion of immature myeloid cells to myeloid-derived suppressor cells (MDSCs), which then inhibit infiltration by cytotoxic T cells and natural killer cells.