Impact of STAT-signaling pathway on cancer-associated fibroblasts in colorectal cancer and its role in immunosuppression

Figure 3 Plasticity between cancer-associated fibroblasts[117]. A: This model demonstrates the antagonistic signaling pathway that determines the ability of cancer-associated fibroblasts (CAFs) to transform into tumor or inflammatory promoter phenotypes. Two subtypes of CAF have been reported in the different zones within the tumor microenvironment in pancreatic ductal adenocarcinoma; inflammatory tumor-associated fibroblasts located in the tumor periphery, and tumor-promoting myofibrolasts (myCAFs) close to the tumor; B: Tumor cells secrete transforming growth factor β ligand (TGF-βL), which allows activation of TGF-β receptor (TGF-βR) in adjacent myCAFs, inhibiting interleukin 1 receptor type 1 (IL-1R1) expression; C: Tumor cells secrete IL-1 alpha (IL-1α) which activates the IL-1 signaling pathway in CAFs. IL-1 signaling induces a cytokine cascade that includes IL-6 and C-X-C chemokine ligand 1, allowing activation of Janus kinase/transcription signaling pathway (JAK/STAT) signaling through nuclear factor kappa B and autocrine leukemia inhibitory factor signaling. Activated JAK/STAT signaling establishes a positive feedback loop involving transcription signaling pathway 3 (STAT3) by upregulation of IL-1R1 expression. Created with BioRender.com. iCAF: Inflammatory tumor-associated fibroblasts; IL: Interleukin; JAK/STAT: Janus kinase/transcription signaling pathway; myCAFs: Tumor-promoting myofibrolasts; LIF: Leukemia inhibitory factor; CXCL: C-X-C chemokine ligand; TGF-β: Transforming growth factor β; NF-κB: Nuclear factor kappa B. Citation: Biffi G, Oni TE, Spielman B, Hao Y, Elyada E, Park Y, Preall J, Tuveson DA. IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma. Cancer Discovery 2019; 9 (2): 282-301, with permission from American Association for Cancer Research (Supplementary material).