1. Macrophage-fibroblast JAK/STAT dependent crosstalk promotes liver metastatic outgrowth in pancreatic cancer.
- Author
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Raymant M, Astuti Y, Alvaro-Espinosa L, Green D, Quaranta V, Bellomo G, Glenn M, Chandran-Gorner V, Palmer DH, Halloran C, Ghaneh P, Henderson NC, Morton JP, Valiente M, Mielgo A, and Schmid MC
- Subjects
- Animals, Humans, Mice, Cell Line, Tumor, Signal Transduction, Janus Kinases metabolism, Mice, Inbred C57BL, Fibroblasts metabolism, Fibroblasts pathology, Male, Cancer-Associated Fibroblasts metabolism, Cancer-Associated Fibroblasts pathology, Female, Pancreatic Neoplasms pathology, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms genetics, Pancreatic Neoplasms immunology, Liver Neoplasms secondary, Liver Neoplasms metabolism, Liver Neoplasms genetics, Liver Neoplasms pathology, Liver Neoplasms immunology, STAT3 Transcription Factor metabolism, STAT3 Transcription Factor genetics, Macrophages metabolism, Macrophages immunology, Carcinoma, Pancreatic Ductal pathology, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal immunology
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease for which better therapies are urgently needed. Fibroblasts and macrophages are heterogeneous cell populations able to enhance metastasis, but the role of a macrophage-fibroblast crosstalk in regulating their pro-metastatic functions remains poorly understood. Here we deconvolve how macrophages regulate metastasis-associated fibroblast (MAF) heterogeneity in the liver. We identify three functionally distinct MAF populations, among which the generation of pro-metastatic and immunoregulatory myofibroblastic-MAFs (myMAFs) critically depends on macrophages. Mechanistically, myMAFs are induced through a STAT3-dependent mechanism driven by macrophage-derived progranulin and cancer cell-secreted leukaemia inhibitory factor (LIF). In a reciprocal manner, myMAF secreted osteopontin promotes an immunosuppressive macrophage phenotype resulting in the inhibition of cytotoxic T cell functions. Pharmacological blockade of STAT3 or myMAF-specific genetic depletion of STAT3 restores an anti-tumour immune response and reduces metastases. Our findings provide molecular insights into the complex macrophage-fibroblast interactions in tumours and reveal potential targets to inhibit PDAC liver metastasis., (© 2024. The Author(s).) more...
- Published
- 2024
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