Astuti, Yuliana, Raymant, Meirion, Quaranta, Valeria, Clarke, Kim, Abudula, Maidinaimu, Smith, Olivia, Bellomo, Gaia, Chandran-Gorner, Vatshala, Nourse, Craig, Halloran, Christopher 
ORCID: 0000-0002-5471-4178 et al (show 8 more authors)
(2024)
Efferocytosis reprograms the tumor microenvironment to promote pancreatic cancer liver metastasis.
Nature cancer.
pp. 1-17.
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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<sup>+</sup> 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: | Article |
|---|---|
| Uncontrolled Keywords: | Rare Diseases, Pancreatic Cancer, Liver Disease, Cancer, Digestive Diseases, 2 Aetiology, 2.1 Biological and endogenous factors |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 22 Jan 2024 09:51 |
| Last Modified: | 12 Apr 2024 02:08 |
| DOI: | 10.1038/s43018-024-00731-2 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3177921 |
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