Astuti, Y. et al. (2024) Efferocytosis reprograms the tumor microenvironment to promote pancreatic cancer liver metastasis. Nature Cancer, (doi: 10.1038/s43018-024-00731-2) (PMID:38355776) (Early Online Publication)
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Abstract
Pancreatic ductal adenocarcinoma is a highly metastatic disease and macrophages support liver metastases. Efferocytosis, or engulfment of apoptotic cells by macrophages, is an essential process in tissue homeostasis and wound healing, but its role in metastasis is less well understood. Here, we found that the colonization of the hepatic metastatic site is accompanied by low-grade tissue injury and that efferocytosis-mediated clearance of parenchymal dead cells promotes macrophage reprogramming and liver metastasis. Mechanistically, progranulin expression in macrophages is necessary for efficient efferocytosis by controlling lysosomal acidification via cystic fibrosis transmembrane conductance regulator and the degradation of lysosomal cargo, resulting in LXRα/RXRα-mediated macrophage conversion and upregulation of arginase 1. Pharmacological blockade of efferocytosis or macrophage-specific genetic depletion of progranulin impairs macrophage conversion, improves CD8+ T cell functions, and reduces liver metastasis. Our findings reveal how hard-wired functions of macrophages in tissue repair contribute to liver metastasis and identify potential targets for prevention of pancreatic ductal adenocarcinoma liver metastasis.
| Item Type: | Articles |
|---|---|
| Additional Information: | These studies were supported by grants from CRUK (A25607, A26978 and A26979), the Medical Research Council (MR/P018920/1) and North West Cancer Research Fund for M.C.S, Wellcome Trust (102521/Z/13/Z) and North West Cancer Research Fund to A.M. and CRUK A17196, A2996 and A25233 to J.P.M. |
| Keywords: | Cancer Research, Oncology |
| Status: | Early Online Publication |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Nourse, Dr Craig and Morton, Dr Jennifer |
| Authors: | Astuti, Y., Raymant, M., Quaranta, V., Clarke, K., Abudula, M., Smith, O., Bellomo, G., Chandran-Gorner, V., Nourse, C., Halloran, C., Ghaneh, P., Palmer, D., Jones, R. P., Campbell, F., Pollard, J. W., Morton, J. P., Mielgo, A., and Schmid, M. C. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Nature Cancer |
| Publisher: | Nature Research |
| ISSN: | 2662-1347 |
| ISSN (Online): | 2662-1347 |
| Copyright Holders: | Copyright: © The Author(s) 2024 |
| First Published: | First published in Nature Cancer 2024 |
| Publisher Policy: | Reproduced under a Creative Commons licence |
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