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To identify SS\u2010specific mechanosensors without detachment impacts, a microfluidic circulatory system is used to generate arteriosus SS and compare transcriptome profiles of circulating lung cancer cells with suspended cells. Half of the cancer cells can survive SS damage and show higher invasion ability. Mesotrypsin (PRSS3), protease\u2010activated receptor 2 (PAR2), and the subunit of activating protein 1, Fos\u2010related antigen 1 (FOSL1), are upregulated by SS, and their high expression is responsible for promoting invasion and metastasis. SS triggers PRSS3\u00a0to cleave the N\u2010terminal inhibitory domain of PAR2\u00a0within 2\u00a0h. As a G protein\u2010coupled receptor, PAR2\u00a0further activates the G<jats:italic>\u03b1<\/jats:italic><jats:sub>i<\/jats:sub> protein to turn on the Src\u2010ERK\/p38\/JNK\u2010FRA1\/cJUN axis to promote the expression of epithelial\u2013mesenchymal transition markers, and also PRSS3, which facilitates metastasis. Enriched PRSS3, PAR2,\u00a0and FOSL1\u00a0in human tumor samples and their correlations with worse outcomes reveal their clinical significance. PAR2\u00a0may serve as an SS\u2010specific mechanosensor cleavable by PRSS3\u00a0in circulation, which provides new insights for targeting metastasis\u2010initiating CTCs.<\/jats:p>","DOI":"10.1002\/advs.202301059","type":"journal-article","created":{"date-parts":[[2023,7,3]],"date-time":"2023-07-03T09:54:14Z","timestamp":1688378054000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Shear Stress Drives the Cleavage Activation of Protease\u2010Activated Receptor 2 by PRSS3\/Mesotrypsin to Promote Invasion and Metastasis of Circulating Lung Cancer Cells"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2219-071X","authenticated-orcid":false,"given":"Muya","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Faculty of Health Sciences University of Macau  Taipa Macao SAR 999078 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