Fig. 6

Interactions between PDAC cells and the ECM. Collagen (Col) is mainly produced by CAFs and acts on DDR1 to promote tumor proliferation. Col activates MRC1 on the surface of TAMs, which further promotes its production by upregulating ATF4 within CAFs, forming a vicious cycle. In contrast to the tumor-suppressing heterotrimeric Col1 produced by CAFs, tumor cells can produce tumor-promoting homotrimeric Col1. MMP can cleave col1 to produce tumor-promoting cCol1. HA produced by CAFs accumulates massively in the microenvironment and mediates growth-promoting signals by acting on CD44. FAK signaling is activated by integrins and mediates connective tissue formation, immunosuppression, and metastasis. Moreover, tumor cells induce the expression of fibronectin to promote therapeutic resistance. Red arrows represent tumor-promoting processes. Pink circles represent possible treatment strategies. DDR1: discoidin domain receptor 1; FAK: focal adhesion kinase; HA: hyaluronan; Col1: collagens I; MMP: matrix metalloproteinase; LPAR4: lysophosphatidic acid receptor 4; ECM: extracellular matrix; CAF: cancer-associated fibroblast; ATF4: activating transcription factor 4; MRC1: mannose receptor C-type 1; RNS: reactive nitrogen species; TAM: tumor-associated macrophage