Macrophage-fibroblast JAK/STAT dependent crosstalk promotes liver metastatic outgrowth in pancreatic cancer

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 funct...

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Bibliographic Details
Published in:Nature communications Vol. 15; no. 1; pp. 3593 - 22
Main Authors: Raymant, Meirion, Astuti, Yuliana, Alvaro-Espinosa, Laura, Green, Daniel, Quaranta, Valeria, Bellomo, Gaia, Glenn, Mark, Chandran-Gorner, Vatshala, Palmer, Daniel H., Halloran, Christopher, Ghaneh, Paula, Henderson, Neil C., Morton, Jennifer P., Valiente, Manuel, Mielgo, Ainhoa, Schmid, Michael C.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 27.04.2024
Nature Publishing Group
Nature Portfolio
Subjects:
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Adenocarcinoma
Animals
Cancer
Cancer-Associated Fibroblasts - metabolism
Cancer-Associated Fibroblasts - pathology
Carcinoma, Pancreatic Ductal - genetics
Carcinoma, Pancreatic Ductal - immunology
Carcinoma, Pancreatic Ductal - metabolism
Carcinoma, Pancreatic Ductal - pathology
Cell Line, Tumor
Cytotoxicity
Female
Fibroblasts
Fibroblasts - metabolism
Fibroblasts - pathology
Heterogeneity
Humanities and Social Sciences
Humans
Immune response
Immune system
Immunoregulation
Inflammation
Janus Kinases - metabolism
Leukemia
Leukemia inhibitory factor
Liver
Liver Neoplasms - genetics
Liver Neoplasms - immunology
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
Liver Neoplasms - secondary
Lymphocytes
Lymphocytes T
Macrophages
Macrophages - immunology
Macrophages - metabolism
Male
Metastases
Metastasis
Mice
Mice, Inbred C57BL
multidisciplinary
Osteopontin
Pancreatic cancer
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - immunology
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Phenotypes
Populations
Science
Science (multidisciplinary)
Signal Transduction
Stat3 protein
STAT3 Transcription Factor - genetics
STAT3 Transcription Factor - metabolism
Tumor microenvironment
Tumors
ISSN:2041-1723, 2041-1723
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Summary: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. An inflammatory-fibrotic tumor microenvironment supports metastatic disease progression in pancreatic ductal adenocarcinoma (PDAC). Here the authors show that metastasis-infiltrating macrophages influence metastasis-associated fibroblast (MAF) heterogeneity in liver metastatic PDAC, by promoting JAK/STAT signalling pathway activation in MAFs.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-47949-3