ROCK isoforms differentially modulate cancer cell motility by mechanosensing the substrate stiffness

Peng, Yueting; Chen, Zhongyuan; Chen, Yu; Li, Shun; Jiang, Ying; Yang, Hong; Wu, Chunhui; You, Fengming; Zheng, Chuan; Zhu, Jie; Tan, Youhua; Qin, Xiang; Liu, Yiyao

doi:10.1016/j.actbio.2019.02.015

Cited by 99 publications

(66 citation statements)

References 60 publications

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“…On the other hand, results suggest that the stiffness regulates in a similar way TER and that the stiffening of the tumor ECM increases the directionality of cell trajectory independently from cell type and, consequently, cell velocity. This result also gives more insights about previous findings on persistence time [29] and supports previous observation demonstrating that stiff substrates promote directional migration [43]. In particular, it has been demonstrated that substrate stiffness regulates RhoA/ROCK1/p-MLC and RhoA/ROCK2/pcofilin pathways, strongly implicated in the progression and metastasis of many cancers included breast cancer, through the activation of integrin β1 and FAK [44][45][46].…”

Section: Discussionsupporting

confidence: 89%

Investigation of Biophysical Migration Parameters for Normal Tissue and Metastatic Cancer Cells After Radiotherapy Treatment

et al. 2020

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A large body of literature has demonstrated that the mechanical properties of microenvironment have a key role in regulating cancer cell adhesion, motility, and invasion. In this work, we have introduced two additional parameters, named cell trajectory extension and area traveled by cell, to describe the tendency of normal tissue and metastatic cancer cells to move in a directional way when they interact with physio-pathological substrates, characterized by stiffnesses of 1-13 kPa, before and after treatment with 2 doses of X-rays (2 and 10 Gy). We interpreted these data by evaluating also the impact of substrate stiffness on 2 morphological parameters which indicate not only the state of cell adhesion, but also cell polarization, prerequisite to directional movement, and the formation of protrusions over cell perimeters. We believe that a so wide analysis can give an efficient and easily readable overview of effects of radiation therapy on cell-ECM crosstalk when used as therapeutic agent.

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Section: Discussionsupporting

confidence: 89%

Investigation of Biophysical Migration Parameters for Normal Tissue and Metastatic Cancer Cells After Radiotherapy Treatment

et al. 2020

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“…Experiments confirmed that ROCK1, but not ROCK2, acted on the phosphorylation of myosin regulatory light chain, and ROCK2 acted more on the phosphorylation of Cofilin. 40 Cofilin is a low molecular-weight actin-modulating protein, which can inhibit its binding to actin after binding with inositol triphosphate (IP). Ample evidence show that a chemokine receptor activates Phospholipases C, catalyzes decomposition of PIP2 (PIP, hosphatidylinositol biphosphate), produces IP3, binds IP3 receptor, and releases intracellular Ca 2þ from endoplasmic reticulum.…”

Section: Discussionmentioning

confidence: 99%

Chemokine receptor CXCR4 activates the RhoA/ROCK2 pathway in spinal neurons that induces bone cancer pain

Peng

Chen

et al. 2020

Mol Pain

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Background Chemokine receptor CXCR4 has been found to be associated with spinal neuron and glial cell activation during bone cancer pain. However, the underlying mechanism remains unknown. Furthermore, the RhoA/ROCK2 pathway serves as a downstream pathway activated by CXCR4 during bone cancer pain. We first validated the increase in the expressions of CXCR4, p-RhoA, and p-ROCK2 in the spinal dorsal horn of a well-characterized tumor cell implantation-induced cancer pain rat model and how these expressions contributed to the pain behavior in tumor cell implantation rats. We hypothesized that spinal blockade of the CXCR4-RhoA/ROCK2 pathway is a potential analgesic therapy for cancer pain management. Methods Adult female Sprague–Dawley rats (body weight of 180–220 g) and six- to seven-week old female Sprague–Dawley rats (body weight of 80–90 g) were taken. Ascitic cancer cells were extracted from the rats (body weight of 80–90 g) with intraperitoneally implanted Walker 256 mammary gland carcinoma cells. Walker 256 rat mammary gland carcinoma cells were then injected (tumor cell implantation) into the intramedullary space of the tibia to establish a rat model of bone cancer pain. Results We found increased expressions of CXCR4, p-RhoA, and p-ROCK2 in the neurons in the spinal cord. p-RhoA and p-ROCK2 were co-expressed in the neurons and promoted by overexpressed CXCR4. Intrathecal delivery of CXCR4 inhibitor Plerixafor (AMD3100) or ROCK2 inhibitor Fasudil abrogated tumor cell implantation-induced pain hypersensitivity and tumor cell implantation-induced increase in p-RhoA and p-ROCK2 expressions. Intrathecal injection of stromal-derived factor-1, the principal ligand for CXCR4, accelerated p-RhoA expression in naive rats, which was prevented by postadministration of CXCR4 inhibitor Plerixafor (AMD3100) or ROCK2 inhibitor Fasudil. Conclusions Collectively, the spinal RhoA/ROCK2 pathway could be a critical downstream target for CXCR4-mediated neuronal sensitization and pain hypersensitivity in bone cancer pain, and it may serve as a potent therapeutic target for pain treatment.

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“…RHOA subsequently activates diaphanous 1 (DIA1) and RHO-associated coiled-coil-containing protein kinase (ROCK) [ 195 ]. Then, JNK activates CapZ-interacting protein (CapZIP) [ 196 ], ROCK activates mitogen-activated protein kinase (MRLC) [ 197 ], and DAAM activates Profilin [ 198 ]. These PCP effectors lead to the development of lateral asymmetry in epithelial sheets and other structures [ 199 ], as well as cell polarity and migration by remodeling the cytoskeleton [ 200 ] (Fig.…”

Section: Introductionmentioning

confidence: 99%

Wnt signaling in breast cancer: biological mechanisms, challenges and opportunities

et al. 2020

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Wnt signaling is a highly conserved signaling pathway that plays a critical role in controlling embryonic and organ development, as well as cancer progression. Genome-wide sequencing and gene expression profile analyses have demonstrated that Wnt signaling is involved mainly in the processes of breast cancer proliferation and metastasis. The most recent studies have indicated that Wnt signaling is also crucial in breast cancer immune microenvironment regulation, stemness maintenance, therapeutic resistance, phenotype shaping, etc. Wnt/β-Catenin, Wnt–planar cell polarity (PCP), and Wnt–Ca2+ signaling are three well-established Wnt signaling pathways that share overlapping components and play different roles in breast cancer progression. In this review, we summarize the main findings concerning the relationship between Wnt signaling and breast cancer and provide an overview of existing mechanisms, challenges, and potential opportunities for advancing the therapy and diagnosis of breast cancer.

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ROCK isoforms differentially modulate cancer cell motility by mechanosensing the substrate stiffness

Cited by 99 publications

References 60 publications

Investigation of Biophysical Migration Parameters for Normal Tissue and Metastatic Cancer Cells After Radiotherapy Treatment

Investigation of Biophysical Migration Parameters for Normal Tissue and Metastatic Cancer Cells After Radiotherapy Treatment

Chemokine receptor CXCR4 activates the RhoA/ROCK2 pathway in spinal neurons that induces bone cancer pain

Wnt signaling in breast cancer: biological mechanisms, challenges and opportunities

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