IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma

• Published in: Cancer discovery Vol. 9; no. 2; pp. 282 - 301
• Main Authors: Biffi, Giulia, Oni, Tobiloba E, Spielman, Benjamin, Hao, Yuan, Elyada, Ela, Park, Youngkyu, Preall, Jonathan, Tuveson, David A
• Format: Journal Article
• Language: English
• Published: United States 01.02.2019
• Subjects: Animals; Apoptosis; Cancer-Associated Fibroblasts - drug effects; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Proliferation; Female; Humans; Inflammation - drug therapy; Inflammation - metabolism; Inflammation - pathology; Interleukin-1 - pharmacology; Janus Kinase 1 - genetics; Janus Kinase 1 - metabolism; Mice; Mice, Nude; Mutation; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Proto-Oncogene Proteins p21(ras) - genetics; Signal Transduction - drug effects; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; Transforming Growth Factor beta - pharmacology; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - genetics; Xenograft Model Antitumor Assays
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.CD-18-0710

Pancreatic ductal adenocarcinoma (PDAC) is poorly responsive to therapies and histologically contains a paucity of neoplastic cells embedded within a dense desmoplastic stroma. Within the stroma, cancer-associated fibroblasts (CAF) secrete tropic factors and extracellular matrix components, and have been implicated in PDAC progression and chemotherapy resistance. We recently identified two distinct CAF subtypes characterized by either myofibroblastic or inflammatory phenotypes; however, the mechanisms underlying their diversity and their roles in PDAC remain unknown. Here, we use organoid and mouse models to identify TGFβ and IL1 as tumor-secreted ligands that promote CAF heterogeneity. We show that IL1 induces LIF expression and downstream JAK/STAT activation to generate inflammatory CAFs and demonstrate that TGFβ antagonizes this process by downregulating IL1R1 expression and promoting differentiation into myofibroblasts. Our results provide a mechanism through which distinct fibroblast niches are established in the PDAC microenvironment and illuminate strategies to selectively target CAFs that support tumor growth. SIGNIFICANCE: Understanding the mechanisms that determine CAF heterogeneity in PDAC is a prerequisite for the rational development of approaches that selectively target tumor-promoting CAFs. Here, we identify an IL1-induced signaling cascade that leads to JAK/STAT activation and promotes an inflammatory CAF state, suggesting multiple strategies to target these cells . .