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

Author

Listed:
  • 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
    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)

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.

Suggested Citation

  • Meirion Raymant & Yuliana Astuti & Laura Alvaro-Espinosa & Daniel Green & Valeria Quaranta & Gaia Bellomo & Mark Glenn & Vatshala Chandran-Gorner & Daniel H. Palmer & Christopher Halloran & Paula Ghan, 2024. "Macrophage-fibroblast JAK/STAT dependent crosstalk promotes liver metastatic outgrowth in pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47949-3
    DOI: 10.1038/s41467-024-47949-3
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    References listed on IDEAS

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