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      YAP/TAZ Related BioMechano Signal Transduction and Cancer Metastasis


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          Mechanoreciprocity refers to a cell’s ability to maintain tensional homeostasis in response to various types of forces. Physical forces are continually being exerted upon cells of various tissue types, even those considered static, such as the brain. Through mechanoreceptors, cells sense and subsequently respond to these stimuli. These forces and their respective cellular responses are prevalent in regulating everything from embryogenic tissue-specific differentiation, programmed cell death, and disease progression, the last of which being the subject of extensive attention. Abnormal mechanical remodeling of cells can provide clues as to the pathological status of tissues. This becomes particularly important in cancer cells, where cellular stiffness has been recently accepted as a novel biomarker for cancer metastasis. Several studies have also elucidated the importance of cell stiffness in cancer metastasis, with data highlighting that a reversal of tumor stiffness has the capacity to revert the metastatic properties of cancer. In this review, we summarize our current understanding of extracellular matrix (ECM) homeostasis, which plays a prominent role in tissue mechanics. We also describe pathological disruption of the ECM, and the subsequent implications toward cancer and cancer metastasis. In addition, we highlight the most novel approaches toward understanding the mechanisms which generate pathogenic cell stiffness and provide potential new strategies which have the capacity to advance our understanding of one of human-kinds’ most clinically significant medical pathologies. These new strategies include video-based techniques for structural dynamics, which have shown great potential for identifying full-field, high-resolution modal properties, in this case, as a novel application.

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          Most cited references43

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          Tensional homeostasis and the malignant phenotype.

          Tumors are stiffer than normal tissue, and tumors have altered integrins. Because integrins are mechanotransducers that regulate cell fate, we asked whether tissue stiffness could promote malignant behavior by modulating integrins. We found that tumors are rigid because they have a stiff stroma and elevated Rho-dependent cytoskeletal tension that drives focal adhesions, disrupts adherens junctions, perturbs tissue polarity, enhances growth, and hinders lumen formation. Matrix stiffness perturbs epithelial morphogenesis by clustering integrins to enhance ERK activation and increase ROCK-generated contractility and focal adhesions. Contractile, EGF-transformed epithelia with elevated ERK and Rho activity could be phenotypically reverted to tissues lacking focal adhesions if Rho-generated contractility or ERK activity was decreased. Thus, ERK and Rho constitute part of an integrated mechanoregulatory circuit linking matrix stiffness to cytoskeletal tension through integrins to regulate tissue phenotype.
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            Breast cancer metastasis: markers and models.

            Breast cancer starts as a local disease, but it can metastasize to the lymph nodes and distant organs. At primary diagnosis, prognostic markers are used to assess whether the transition to systemic disease is likely to have occurred. The prevailing model of metastasis reflects this view--it suggests that metastatic capacity is a late, acquired event in tumorigenesis. Others have proposed the idea that breast cancer is intrinsically a systemic disease. New molecular technologies, such as DNA microarrays, support the idea that metastatic capacity might be an inherent feature of breast tumours. These data have important implications for prognosis prediction and our understanding of metastasis.
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              Local force and geometry sensing regulate cell functions.

              The shapes of eukaryotic cells and ultimately the organisms that they form are defined by cycles of mechanosensing, mechanotransduction and mechanoresponse. Local sensing of force or geometry is transduced into biochemical signals that result in cell responses even for complex mechanical parameters such as substrate rigidity and cell-level form. These responses regulate cell growth, differentiation, shape changes and cell death. Recent tissue scaffolds that have been engineered at the micro- and nanoscale level now enable better dissection of the mechanosensing, transduction and response mechanisms.

                Author and article information

                Front Cell Dev Biol
                Front Cell Dev Biol
                Front. Cell Dev. Biol.
                Frontiers in Cell and Developmental Biology
                Frontiers Media S.A.
                04 October 2019
                : 7
                : 199
                [1] 1Engineering Institute, Los Alamos National Laboratory , Los Alamos, NM, United States
                [2] 2Applied Modern Physics, Los Alamos National Laboratory , Los Alamos, NM, United States
                [3] 3Department of Medicine, St. George’s University School of Medicine , St. George’s, Grenada
                [4] 4Chemistry Division, Physical Chemistry and Applied Spectroscopy, Los Alamos National Laboratory , Los Alamos, NM, United States
                [5] 5Energy and Global Security, Argonne National Laboratory , Lemont, IL, United States
                Author notes

                Edited by: Selwin Kaixiang Wu, Harvard Medical School, United States

                Reviewed by: Sandeep Kumar Vishwakarma, Deccan College of Medical Sciences, India; Brian A. Wall, Colgate-Palmolive, United States; Lin Deng, Harvard Medical School, United States

                This article was submitted to Cell Adhesion and Migration, a section of the journal Frontiers in Cell and Developmental Biology

                Copyright © 2019 Martinez, Yang, Harker, Farrar, Nath and Mascareñas.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                : 07 January 2019
                : 05 September 2019
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 71, Pages: 7, Words: 0
                Cell and Developmental Biology
                Mini Review

                cancer biology,biomarkers,metastasis and actin dynamics,cell rigidity measurement,cell morphodynamics


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