IL-1-induced JAK/STAT signaling is antagonized by TGF-β to shape CAF heterogeneity in pancreatic ductal adenocarcinoma.

By Giulia Biffi, Tobiloba E. Oni, Benjamin P. Spielman, Yuan Hao, Ela Elyada, Youngkyu Park, Jonathan Preall, D. Tuveson. Cancer Discovery, 2018

998 citations recorded by the source corpus.

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 (CAFs) 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 TGF-β and IL-1 as tumor-secreted ligands that promote CAF heterogeneity. We show that IL-1 induces LIF expression and downstream JAK/STAT activation to generate inflammatory CAFs, and demonstrate that TGF-β antagonizes this process by downregulating IL-1R1 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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/80fe651158817540fc8c6de65b85c7e720d1a2cd

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In Immunology

1. S. Grivennikov
2. F. Greten
3. M. Karin

In Oncology

1. S. Grivennikov
2. F. Greten
3. Xiawei Wei
4. M. Karin

Citations in the corpus

• Targeting TGF-β signal transduction for fibrosis and cancer therapy (2022, background): “ACE-1334 superfamily based ligand trap of TGFβ1 and c3 Systemic Sclerosis With and Without Interstitial Lung Disease Phase 1/Phase 2 NCT04948554 ACE-536 (Luspatercept) TGFβ superfamily ligand trap Myelodysplastic Syndromes Phase2/Phase 3 NCT04477850/ NCT03900715/NCT03682536 Myelodysplastic Syndromes”
• Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments (2023, background): “Rising evidence emphasize different role of specific subtypes of CAFs in pancreatic cancer [32, 33].”
• The JAK/STAT signaling pathway: from bench to clinic (2021, background): “In pancreatic ductal carcinoma, tumor-secreted TGFβ antagonizes the upregulation of LIF induced by IL-1 by downregulating the expression of IL-1R1 and promoting the differentiation of cancerassociated fibroblasts into myofibroblasts, thereby inhibiting JAK/ STAT signaling.(183) In contrast, in hepat”
• Inflammation and Cancer: Triggers, Mechanisms and Consequences (2019, background): “A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript proximity to cancer cells as well as their response to IL-1R engagement or TGFβ activation they may differentiate into inflammatory CAFs (iCAFs) or myofibroblasts (myCAFs) (Biffi et al., 2019; Ohlund et al., 2017).”
• Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer (2021, background): “Accordingly, the high heterogeneity in CAFs raises an interesting question: If CAFs would switch in distinct functional states or subtypes? As an answer to this question, it has been suggested that IL-1 signaling induces the generation of inflammatory CAFs, and TGF-β antagonizes CAF switching from a”