Fluid Shear Stress Induces EMT of Circulating Tumor Cells via JNK Signaling in Favor of Their Survival during Hematogenous Dissemination

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.

Download Full-text

Survival of the resilient: Mechano-adaptation of circulating tumor cells to fluid shear stress

Molecular & Cellular Oncology ◽

10.1080/23723556.2020.1766338 ◽

2020 ◽

Vol 7 (4) ◽

pp. 1766338

Author(s):

Devon L. Moose ◽

Michael D. Henry

Keyword(s):

Shear Stress ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Fluid Shear Stress ◽

Fluid Shear

Download Full-text

Fluid shear stress coupled with narrow constrictions induce cell type-dependent morphological and molecular changes in circulating tumor cells

10.1101/722306 ◽

2019 ◽

Author(s):

Hamizah Ahmad Cognart ◽

Jean-Louis Viovy ◽

Catherine Villard

Keyword(s):

Shear Stress ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Fluid Shear Stress ◽

Dynamical Behavior ◽

Metastatic Breast ◽

Microfluidic Channels ◽

Mechanical Stimuli ◽

Fluid Shear ◽

Mesenchymal Transition

AbstractCancer mortality mainly arises from metastases, due to cells that escape from a primary tumor, circulate in the blood as circulating tumor cells (CTCs), permeate across blood vessels and nest in distant organs. It is still unclear how CTCs overcome the harsh conditions of fluid shear stress and mechanical constraints within the microcirculation. Here, a model of the blood microcirculation was established through the fabrication of microfluidic channels comprising constrictions. Metastatic breast cancer cells of epithelial-like and mesenchymal-like phenotypes were flowed into the microfluidic device. These cells were visualized during circulation, analyzed for their dynamical behavior and retrieved post-circulation. γ-H2AX staining showed significant increase of DNA damage response in epithelial-like SK-BR-3 cells, while gene expression analysis of key regulators of epithelial-to-mesenchymal transition revealed significant increase of Twist2 relative expression in mesenchymal-like MDA-MB-231 cells post-circulation. This work documents first results of the changes at the cellular, subcellular and molecular scales induced by the two main mechanical stimuli arising from circulatory conditions.

Download Full-text

Abstract 3152: RhoA-myosinII axis protects circulating tumor cells from fluid shear stress-induced damage

10.1158/1538-7445.am2018-3152 ◽

2018 ◽

Author(s):

Devon L. Moose ◽

Ben L. Krog ◽

Gretchen Burke ◽

Lei Zhao ◽

Lillian Rhodes ◽

...

Keyword(s):

Shear Stress ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Fluid Shear Stress ◽

Fluid Shear

Download Full-text

Role of cadherins and plakoglobin in interendothelial adhesion under resting conditions and shear stress

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.273.5.h2396 ◽

1997 ◽

Vol 273 (5) ◽

pp. H2396-H2405 ◽

Cited By ~ 20

Author(s):

Hans-Joachim Schnittler ◽

Bernd Püschel ◽

Detlev Drenckhahn

Keyword(s):

Endothelial Cells ◽

Shear Stress ◽

Time Course ◽

Fluid Shear Stress ◽

Vascular Endothelial ◽

Fluid Shear ◽

Platelet Endothelial Cell Adhesion ◽

Cell Adhesion Molecule 1 ◽

Arterial Endothelial Cells

The role of cadherins and the cadherin-binding cytosolic protein plakoglobin in intercellular adhesion was studied in cultured human umbilical venous endothelial cells exposed to fluid shear stress. Extracellular Ca2+depletion (<10−7 M) caused the disappearance of both cadherins and plakoglobin from junctions, whereas the distribution of platelet endothelial cell adhesion molecule 1 (PECAM-1) remained unchanged. Cells stayed fully attached to each other for several hours in low Ca2+ but began to dissociate under flow conditions. At the time of recalcification, vascular endothelial (VE) cadherin and β-catenin became first visible at junctions, followed by plakoglobin with a delay of ∼20 min. Full fluid shear stress stability of the junctions correlated with the time course of the reappearance of plakoglobin. Inhibition of plakoglobin expression by microinjection of antisense oligonucleotides did not interfere with the junctional association of VE-cadherin, PECAM-1, and β-catenin. The plakoglobin-deficient cells remained fully attached to each other under resting conditions but began to dissociate in response to flow. Shear stress-induced junctional dissociation was also observed in cultures of plakoglobin-depleted arterial endothelial cells of the porcine pulmonary trunk. These observations show that interendothelial adhesion under hydrodynamic but not resting conditions requires the junctional location of cadherins associated with plakoglobin. β-Catenin cannot functionally compensate for the junctional loss of plakoglobin, and PECAM-1-mediated adhesion is not sufficient for monolayer integrity under flow.

Download Full-text

Pattern formation of vascular smooth muscle cells subject to nonuniform fluid shear stress: role of PDGF-β receptor and Src

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00434.2003 ◽

2003 ◽

Vol 285 (3) ◽

pp. H1081-H1090 ◽

Cited By ~ 11

Author(s):

Shu Q. Liu ◽

Christopher Tieche ◽

Dalin Tang ◽

Paul Alkema

Keyword(s):

Shear Stress ◽

Smooth Muscle ◽

Cell Density ◽

Fluid Shear Stress ◽

Density Gradients ◽

Dependent Manner ◽

Fluid Shear ◽

Polymer Implants ◽

Β Receptor

Blood vessels are subject to fluid shear stress, a hemodynamic factor that inhibits the mitogenic activities of vascular cells. The presence of nonuniform shear stress has been shown to exert graded suppression of cell proliferation and induces the formation of cell density gradients, which in turn regulate the direction of smooth muscle cell (SMC) migration and alignment. Here, we investigated the role of platelet-derived growth factor (PDGF)-β receptor and Src in the regulation of such processes. In experimental models with vascular polymer implants, SMCs migrated from the vessel media into the neointima of the implant under defined fluid shear stress. In a nonuniform shear model, blood shear stress suppressed the expression of PDGF-β receptor and the phosphorylation of Src in a shear level-dependent manner, resulting in the formation of mitogen gradients, which were consistent with the gradient of cell density as well as the alignment of SMCs. In contrast, uniform shear stress in a control model elicited an even influence on the activity of mitogenic molecules without modulating the uniformity of cell density and did not significantly influence the direction of SMC alignment. The suppression of the PDGF-β receptor tyrosine kinase and Src with pharmacological substances diminished the gradients of mitogens and cell density and reduced the influence of nonuniform shear stress on SMC alignment. These observations suggest that PDGF-β receptor and Src possibly serve as mediating factors in nonuniform shear-induced formation of cell density gradients and alignment of SMCs in the neointima of vascular polymer implants.

Download Full-text