IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma
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Abstract
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 in vivo. See related commentary by Ling and Chiao, p. 173. This article is highlighted in the In This Issue feature, p. 151
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Fibroblasts coordinate the function of the immune system via production of chemokines and cytokines, with heterogeneity in cytokines produced by different fibroblasts.
“coordinate the function of the immune system via the production of chemokines and cytokines, although it should be noted that there is heterogeneity in the cytokines produced by different fibroblasts16–20.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [20]
The Results section on IL-1 signaling reports that pancreatic fibroblasts increase expression of inflammatory cytokines and chemokines, and the Introduction distinguishes inflammatory from myofibroblastic CAFs. The Discussion suggests that the secretory phenotype of inflammatory CAFs may contribute to immune suppression, but does not establish the broader claim that fibroblasts coordinate immune-system function. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCAFs isolated from mouse PDAC can be switched from αSMA-high and IL-6-producing states through manipulation of TGFβ and IL-1 signalling, indicating considerable plasticity in fibroblast states.
“CAFs isolated from mouse PDAC can be switched from the αSMA-high and IL-6-producing states through manipulation of TGFβ and IL-1 signalling, arguing for considerable plasticity in fibroblast states20.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [20]
The Results sections on IL-1 signaling and TGF-β antagonism report changes in IL-6 and αSMA-associated markers when those pathways are manipulated in cultured pancreatic stellate cells. The Discussion describes iCAFs and myCAFs as potentially interconvertible. However, the switching experiments described use stellate cells cultured to model CAF states, not CAFs isolated from mouse PDAC, so that experimental detail is not supported. (LLM, conf=0.84)
Experimental — accuracy not yet measuredActivation of IL1/LIF/JAK/STAT signaling generates inflammatory CAFs, while TGFβ signaling antagonizes this process by downregulating IL1R1 expression and promoting differentiation into myofibroblasts.
“In this report, activation of IL1/leukemia inhibitory factor (LIF)/janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling generate inflammatory CAFs while TGFβ signaling antagonizes this process by downregulating interleukin 1 receptor, type I (IL1R1) expression and promoting differentiation into myofibroblasts [73].”
From Tumor microenvironment complexity and therapeutic implications at a glance (2020) · cites this paper as [73]
3D cancer models show selective control of CAF function by tumor cells.
“In addition to the findings from the regular cancer models, the 3D cancer models showed an obvious case of selective control of CAF function by TCs.”
From Tumor microenvironment complexity and therapeutic implications at a glance (2020) · cites this paper as [73]
The apparent exclusivity of the myoCAF and iCAF phenotypes can be explained by TGFβ-mediated suppression of the IL-1 receptor, which is responsible for driving NF-κB signalling and subsequent IL-6 expression.
“The apparent exclusivity of the two phenotypes can be explained by TGFβ-mediated suppression of the IL-1 receptor, which is responsible for driving NF-κB signalling and subsequent IL-6 expression20.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [20]
MyCAFs localize near neoplastic cells and are thought to deposit extracellular matrix, whereas iCAFs occupy spaces between PDAC cell islands and release IL6 and other anti-inflammatory cytokines.
“MyCAFs are localized close to the neoplastic cells and thought to be responsible for deposition of extracellular matrix, whereas iCAFs tend to occupy spaces between islands of the PDAC cells and release IL6 and other anti-inflammatory cytokines.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [147]
MyCAF and iCAF populations have been identified among CAFs.
“Early efforts to identify and understand different CAF populations identified a myofibroblast-like population (myCAF) and an inflammatory fibroblast population (iCAF)147”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [147]
The majority of collagen in PDAC is type I collagen, largely generated by CAFs.
“The majority of collagen is type I collagen164, largely generated by CAFs147,165”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [147]
Pancreatic CAFs are in close proximity to PDAC cells.
“Pancreatic CAFs are in close proximity to PDAC cells147.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [147]
It may also explain the expression and functions of EMT transcription factors in a fraction of stromal fibroblasts.
“It may also explain the expression and functions of EMT transcription factors in a fraction of stromal fibroblasts253,254.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [254]
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“In this report, activation of IL1/ leukemia inhibitory factor (LIF)/janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling generate inflammatory CAFs while TGFβ signaling antagonizes this process by downregulating interleukin 1 receptor, type I (IL1R1) expression and promoting differentia…”
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“populations with potentially distinct functions and activation pathways.(14,15,20) Here, we sought to determine which fibroblasts in the”
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Why is pancreatic cancer so deadly? The pathologist's view
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Epithelial and stromal co-evolution and complicity in pancreatic cancer
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“Conversely, TGF-β counters this process and facilitates the conversion of myCAFs [129].”
BackgroundExtrinsic KRAS signaling shapes the pancreatic microenvironment through fibroblast reprogramming
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“In comparison, we found that IL-1 induced IL-6 in an NF-jB-dependent manner (Fig 3H), consistent with prior results (Biffi et al, 2019).”
BackgroundResultInfluentialFibroblasts as Modulators of Local and Systemic Cancer Metabolism
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Pre-clinical Models of Metastasis in Pancreatic Cancer
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Organoid co‐culture models of the tumor microenvironment promote precision medicine
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- Authors
- Biffi, G., Oni, T. E., Spielman, B., Hao, Y., Elyada, E., Park, Y., Preall, J., & Tuveson, D. A.
- Affiliations
- Cold Spring Harbor Laboratory (US)
- 1Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
- Corresponding author
- Tuveson, David A.
- Venue
- Cancer Discovery
- Published
- 2019-02-01
- Volume
- 9
- Issue
- 2
- Pages
- 282-301
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC6368881
- OpenAlex
- W2898435366
- Cited by
- 1,360
- References
- 56
- Citations by year
- 2026: 219 · 2025: 193 · 2024: 190 · 2023: 189 · 2022: 208 · 2021: 167 · 2020: 135 · 2019: 56 · 2018: 3
- FWCI
- 33.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- Funders
- NIH (5P30CA045508)
- Cold Spring Harbor Laboratory Association and the National Institutes of Health (NIH 5P30CA45508, 5P50CA101955, P20CA192996, U10CA180944, U01CA210240, U01CA224013, 1R01CA188134, and 1R01CA190092)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Keywords
- pancreatic ductal adenocarcinoma, cancer-associated fibroblasts, CAF heterogeneity, interleukin-1, TGF-beta, JAK/STAT signaling, IL1R1, LiF, myofibroblast differentiation, tumor microenvironment, desmoplasia, organoids, chemoresistance
- MeSH terms
- Cancer-Associated Fibroblasts, Animals, Female, Humans, Inflammation, Interleukin-1, Mice, Nude, Mutation, Pancreatic Neoplasms, Tumor Cells, Cultured, Signal Transduction, Tumor Suppressor Protein p53, Transforming Growth Factor beta, Proto-Oncogene Proteins p21(ras), Apoptosis, Carcinoma, Pancreatic Ductal, Xenograft Model Antitumor Assays, Cell Proliferation, STAT1 Transcription Factor, Mice, Janus Kinase 1
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