2026-04-29T22:57:48Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/255222025-12-18T12:56:59Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc 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 author 2024-04-27 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. Nat Commun . 2024 Apr 27;15(1):3593. Nature Communications 38678021 https://hdl.handle.net/20.500.12105/25522 HEPATIC STELLATE CELLS TUMOR-GROWTH SUPPRESSION INHIBITION RESISTANCE Macrophage-fibroblast JAK/STAT dependent crosstalk promotes liver metastatic outgrowth in pancreatic cancer.