2026-04-29T22:57:50Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/255222025-12-18T12:56:59Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Raymant, Meirion
author
Astuti, Yuliana
author
Alvaro-Espinosa, Laura
author
Green, Daniel
author
Quaranta, Valeria
author
Bellomo, Gaia
author
Glenn, Mark
author
Chandran-Gorner, Vatshala
author
Palmer, Daniel H
author
Halloran, Christopher
author
Ghaneh, Paula
author
Henderson, Neil C
author
Morton, Jennifer P
author
Valiente, Manuel
author
Mielgo, Ainhoa
author
Schmid, Michael C
funder
Cancer Research UK
funder
Cell Sorting Facility (CSF)
funder
Centre for Genomic Research
funder
Medical Research Council UK (MRC)
funder
UK Research & Innovation (UKRI)
funder
North West Cancer Research Fund
funder
Wellcome Trust
2024-11-18T11:58:17Z
2024-11-18T11:58:17Z
2024-04-27
Nat Commun . 2024 Apr 27;15(1):3593.
Nature Communications
38678021
https://hdl.handle.net/20.500.12105/25522
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.
eng
HEPATIC STELLATE CELLS
TUMOR-GROWTH
SUPPRESSION
INHIBITION
RESISTANCE
Macrophage-fibroblast JAK/STAT dependent crosstalk promotes liver metastatic outgrowth in pancreatic cancer.
research article
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URL
https://repisalud.isciii.es/bitstreams/e4d92922-b749-4d17-b71a-98f539ecd8ab/download
File
MD5
ac6e0f620ccbb377a84fb47d43202e21
5903857
application/pdf
MacrophagefibroblastJAKSTAT-2024.pdf