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

Meirion Raymant, Yuliana Astuti, Laura Alvaro-Espinosa, Daniel Green, Valeria Quaranta, Gaia Bellomo, Mark Glenn, Vatshala Chandran-Gorner, Daniel H. Palmer, Christopher Halloran, Paula Ghaneh, Neil C. Henderson, Jennifer P. Morton, Manuel Valiente, Ainhoa Mielgo and Michael C. Schmid ()
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Meirion Raymant: University of Liverpool
Yuliana Astuti: University of Liverpool
Laura Alvaro-Espinosa: Spanish National Cancer Research Centre (CNIO)
Daniel Green: University of Liverpool
Valeria Quaranta: University of Liverpool
Gaia Bellomo: University of Liverpool
Mark Glenn: University of Liverpool
Vatshala Chandran-Gorner: University of Liverpool
Daniel H. Palmer: University of Liverpool
Christopher Halloran: University of Liverpool
Paula Ghaneh: University of Liverpool
Neil C. Henderson: University of Edinburgh
Jennifer P. Morton: University of Glasgow
Manuel Valiente: Spanish National Cancer Research Centre (CNIO)
Ainhoa Mielgo: University of Liverpool
Michael C. Schmid: University of Liverpool

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47949-3

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