Journal article
Activation of p38α stress-activated protein kinase drives the formation of the pre-metastatic niche in the lungs
Nature cancer, Vol.1(6), pp.603-619
06/01/2020
DOI: 10.1038/s43018-020-0064-0
PMCID: PMC8194112
PMID: 34124690
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.
Details
- Title: Subtitle
- Activation of p38α stress-activated protein kinase drives the formation of the pre-metastatic niche in the lungs
- Creators
- Jun Gui - University of PennsylvaniaFarima Zahedi - University of PennsylvaniaAngelica Ortiz - University of PennsylvaniaChristina Cho - University of PennsylvaniaKanstantsin V Katlinski - University of PennsylvaniaKevin Alicea-Torres - The Wistar InstituteJinyang Li - University of PennsylvaniaLeslie Todd - University of PennsylvaniaHongru Zhang - University of PennsylvaniaDaniel P Beiting - University of PennsylvaniaCindy Sander - University of PittsburghJohn M Kirkwood - University of PittsburghBryan E Snow - Princess Margaret Cancer CentreAndrew C Wakeham - Princess Margaret Cancer CentreTak W Mak - Princess Margaret Cancer CentreJ Alan Diehl - Case Western Reserve UniversityConstantinos Koumenis - University of PennsylvaniaSandra W Ryeom - University of PennsylvaniaBen Z Stanger - University of PennsylvaniaEllen Puré - University of PennsylvaniaDmitry I Gabrilovich - The Wistar InstituteSerge Y Fuchs - University of Pennsylvania
- Resource Type
- Journal article
- Publication Details
- Nature cancer, Vol.1(6), pp.603-619
- DOI
- 10.1038/s43018-020-0064-0
- PMID
- 34124690
- PMCID
- PMC8194112
- NLM abbreviation
- Nat Cancer
- ISSN
- 2662-1347
- eISSN
- 2662-1347
- Grant note
- R01 CA216936 / NCI NIH HHS P01 CA165997 / NCI NIH HHS R01 CA092900 / NCI NIH HHS R01 CA229803 / NCI NIH HHS P50 CA121973 / NCI NIH HHS T32 CA009140 / NCI NIH HHS F32 CA206431 / NCI NIH HHS
- Language
- English
- Date published
- 06/01/2020
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984949511402771
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