Abstract
Tumor cells metastasize to distal organs mainly through hematogenous dissemination, where they experience considerable levels of fluid shear stress. Epithelial–mesenchymal transition (EMT) plays a critical role in tumor metastasis. However, how fluid shear stress influences the EMT phenotype of circulating tumor cells (CTCs) in suspension has not been fully understood. The role of shear-induced EMT in cell survival under blood shear flow remains unclear. This study shows that the majority of breast CTCs underwent apoptosis under shear flow and the surviving cells exhibited mesenchymal phenotype, suggesting that fluid shear stress induces EMT. Mechanistically, fluid shear stress-activated Jun N-terminal kinase (JNK) signaling, inhibition/activation of which suppressed/promoted the EMT phenotype. In particular, shear flow facilitated the JNK-dependent transition of epithelial CTCs into the mesenchymal status and maintained the pre-existing mesenchymal cells. Importantly, the induction of EMT suppressed the pro-apoptosis gene p53 upregulated modulator of apoptosis (PUMA) and enhanced the survival of suspended CTCs in fluid shear stress, which was rescued by overexpressing PUMA or silencing JNK signaling, suggesting that shear-induced EMT promotes CTC survival through PUMA downregulation and JNK activation. Further, the expressions of EMT markers and JUN were correlated with poor patient survival. In summary, our findings have demonstrated that fluid shear stress induces EMT in suspended CTCs via JNK signaling that promotes their survival in shear flow. This study thus unveils a new role of blood shear stress in CTC survival and facilitates the development of novel therapeutics against tumor metastasis.
Highlights
Cancer has become the second leading cause of human deaths globally, and over 90% of cancer-related deaths are attributed to metastatic dissemination
Our results have demonstrated that fluid shear stress facilitates the transition of epithelial circulating tumor cells (CTCs) into mesenchymal status, which further promotes their survival in blood shear flow via p53 upregulated modulator of apoptosis (PUMA) and Jun N-terminal kinase (JNK) signaling
It has been demonstrated that mechanical signals, including fluid shear stress, influence the Epithelial–Mesenchymal Transition (EMT) phenotype of tumor cells, the majority of which have focused on tumor cells that are attached to solid substrates [26,43]
Summary
Cancer has become the second leading cause of human deaths globally, and over 90% of cancer-related deaths are attributed to metastatic dissemination. Metastasis is a complex and sequential process, which mainly includes cell detachment from the primary tumor, local invasion, intravasation into and survival in the vasculature, extravasation into distal organs, and formation of metastatic lesions [1]. Tumor cells metastasize to distal organs mainly through hematogenous dissemination. The survival of circulating tumor cells (CTCs) in the vasculature is critical for the efficiency of the entire metastasis process. After exiting the protective primary tumor microenvironment and entering the vasculature, CTCs become suspended and vulnerable to various factors in blood circulation. There still exists a small subpopulation of CTCs that can survive hematogenous dissemination and eventually generate metastases in distal organs [1]. It is essential to unveil the survival mechanisms of tumor cells during blood circulation for the effective prevention of metastasis
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