Mesothelin secretion by pancreatic cancer cells co-opts macrophages and promotes metastasis

Mielgo Iza, Ainhoa ORCID: 0000-0002-4159-5931 (2024) Mesothelin secretion by pancreatic cancer cells co-opts macrophages and promotes metastasis. Cancer Research, 84 (4). pp. 527-544.

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Official URL: http://dx.doi.org/10.1158/0008-5472.can-23-1542

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease, yet effective treatments to inhibit PDAC metastasis are lacking. The rich PDAC tumor microenvironment plays a major role in disease progression. Macrophages are the most abundant immune cell population in PDAC tumors and can acquire a range of functions that either hinder or promote tumor growth and metastasis. Here, we identified that mesothelin secretion by pancreatic cancer cells co-opts macrophages to support tumor growth and metastasis of cancer cells to the lungs, liver, and lymph nodes. Mechanistically, secretion of high levels of mesothelin by metastatic cancer cells induced the expression of VEGF alpha (VEGFA) and S100A9 in macrophages. Macrophage-derived VEGFA fed back to cancer cells to support tumor growth, and S100A9 increased neutrophil lung infiltration and formation of neutrophil extracellular traps. These results reveal a role for mesothelin in regulating macrophage functions and interaction with neutrophils to support PDAC metastasis.<h4>Significance</h4>Mesothelin secretion by cancer cells supports pancreatic cancer metastasis by inducing macrophage secretion of VEGFA and S100A9 to support cancer cell proliferation and survival, recruit neutrophils, and stimulate neutrophil extracellular trap formation. See related commentary by Alewine, p. 513.

Item Type:	Article
Uncontrolled Keywords:	Cell Line, Tumor, Macrophages, Humans, Carcinoma, Pancreatic Ductal, Pancreatic Neoplasms, Tumor Microenvironment, Mesothelin
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:	16 Feb 2024 11:00
Last Modified:	01 Mar 2024 10:27
DOI:	10.1158/0008-5472.CAN-23-1542
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3178736