| Literature DB >> 34124690 |
Jun Gui1, Farima Zahedi1, Angelica Ortiz1, Christina Cho1, Kanstantsin V Katlinski1, Kevin Alicea-Torres2, Jinyang Li3, Leslie Todd1, Hongru Zhang1, Daniel P Beiting4, Cindy Sander5, John M Kirkwood5, Bryan E Snow6, Andrew C Wakeham6, Tak W Mak6, J Alan Diehl7, Constantinos Koumenis8, Sandra W Ryeom9, Ben Z Stanger3, Ellen Puré1, Dmitry I Gabrilovich2, Serge Y Fuchs10.
Abstract
Primary tumor-derived factors (TDFs) act upon normal cells to generate a pre-metastatic niche, which promotes colonization of target organs by disseminated malignant cells. Here we report that TDFs-induced activation of the p38α kinase in lung fibroblasts plays a critical role in the formation of a pre-metastatic niche in the lungs and subsequent pulmonary metastases. Activation of p38α led to inactivation of type I interferon signaling and stimulation of expression of fibroblast activation protein (FAP). FAP played a key role in remodeling of the extracellular matrix as well as inducing the expression of chemokines that enable lung infiltration by neutrophils. Increased activity of p38 in normal cells was associated with metastatic disease and poor prognosis in human melanoma patients whereas inactivation of p38 suppressed lung metastases. We discuss the p38α-driven mechanisms stimulating the metastatic processes and potential use of p38 inhibitors in adjuvant therapy of metastatic cancers.Entities:
Keywords: IFNAR1; adjuvant therapy; fibroblast activation protein; interferon; lung metastasis; melanoma; metastatic cancer; p38 inhibitor; p38 kinase; pancreatic ductal adenocarcinoma; pre-metastatic niche; tumor-derived factors
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Year: 2020 PMID： 34124690 PMCID： PMC8194112 DOI： 10.1038/s43018-020-0064-0
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347