To study how cancer cells can withstand fluid shear stress (SS), we isolated SS-resistant breast and lung cancer cells using a microfluidic circulatory system. These SS-resistant cells showed higher abilities to form clusters, survive in circulation, and metastasize in mice. These SS-resistant cells expressed 4.2-to 5.3-fold more desmocollin-2 (DSC2) and plakophilin-1 (PKP1) proteins. The high expression of DSC2 and PKP1 facilitated cancer cells to form clusters in circulation, and also activated PI3K/AKT/Bcl-2-mediated pathway to increase cell survival. The high levels of DSC2 and PKP1 are also important for maintaining high expression of vimentin, which stimulates fibronectin/ integrin  1 /FAK/Src/MEK/ERK/ZEB1-mediated metastasis. Moreover, higher levels of DSC2 and PKP1 were detected in tumor samples from patients with breast and lung cancer, and their high expression was correlated with lower overall survival and worse disease progression. DSC2 and PKP1 may serve as new biomarkers for detecting and targeting metastatic circulating tumor cells.

No abstract

When circulating tumor cells (CTCs) travel in circulation, they can be killed by detachment‐induced anoikis and fluidic shear stress (SS)‐mediated apoptosis. Circulatory treatment, which can make CTCs detached but also generate SS, can increase metastasis of cancer cells. To identify SS‐specific 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‐activated receptor 2 (PAR2), and the subunit of activating protein 1, Fos‐related antigen 1 (FOSL1), are upregulated by SS, and their high expression is responsible for promoting invasion and metastasis. SS triggers PRSS3 to cleave the N‐terminal inhibitory domain of PAR2 within 2 h. As a G protein‐coupled receptor, PAR2 further activates the Gαi protein to turn on the Src‐ERK/p38/JNK‐FRA1/cJUN axis to promote the expression of epithelial–mesenchymal transition markers, and also PRSS3, which facilitates metastasis. Enriched PRSS3, PAR2, and FOSL1 in human tumor samples and their correlations with worse outcomes reveal their clinical significance. PAR2 may serve as an SS‐specific mechanosensor cleavable by PRSS3 in circulation, which provides new insights for targeting metastasis‐initiating CTCs.