Advertisement

Cancer as a biophysical disease: Targeting the mechanical-adaptability program

      Abstract

      With the number of cancer cases projected to significantly increase over time, researchers are currently exploring “nontraditional” research fields in the pursuit of novel therapeutics. One emerging area that is steadily gathering interest revolves around cellular mechanical machinery. When looking broadly at the physical properties of cancer, it has been debated whether a cancer could be defined as either stiffer or softer across cancer types. With numerous articles supporting both sides, the evidence instead suggests that cancer is not particularly regimented. Instead, cancer is highly adaptable, allowing it to endure the constantly changing microenvironments cancer cells encounter, such as tumor compression and the shear forces in the vascular system and body. What allows cancer cells to achieve this adaptability are the particular proteins that make up the mechanical network, leading to a particular mechanical program of the cancer cell. Coincidentally, some of these proteins, such as myosin II, α-actinins, filamins, and actin, have either altered expression in cancer and/or some type of direct involvement in cancer progression. For this reason, targeting the mechanical system as a therapeutic strategy may lead to more efficacious treatments in the future. However, targeting the mechanical program is far from trivial. As involved as the mechanical program is in cancer development and metastasis, it also helps drive many other key cellular processes, such as cell division, cell adhesion, metabolism, and motility. Therefore, anti-cancer treatments targeting the mechanical program must take great care to avoid potential side effects. Here, we introduce the potential of targeting the mechanical program while also providing its challenges and shortcomings as a strategy for cancer treatment.

      Keyword s

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Cell
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Luo T.
        • Mohan K.
        • Robinson D.N.
        • et al.
        Molecular mechanisms of cellular mechanosensing.
        Nat. Mater. 2013; 12: 1064-1071https://doi.org/10.1038/nmat3772
        • Surcel A.
        • Schiffhauer E.S.
        • Robinson D.N.
        • et al.
        Targeting mechanoresponsive proteins in pancreatic cancer: 4-hydroxyacetophenone blocks dissemination and invasion by activating MYH14.
        Cancer Res. 2019; 79: 4665-4678https://doi.org/10.1158/0008-5472.CAN-18-3131
        • Parajon E.
        • Surcel A.
        • Robinson D.N.
        The mechanobiome: a goldmine for cancer therapeutics.
        Am. J. Physiol. Cell Physiol. 2021; 320: C306-C323https://doi.org/10.1152/ajpcell.00409.2020
        • Brahimi-Horn M.C.
        • Chiche J.
        • Pouyssegur J.
        Hypoxia and cancer.
        J. Mol. Med. (Berl). 2007; 85: 1301-1307https://doi.org/10.1007/s00109-007-0281-3
        • Vaupel P.
        • Hockel M.
        • Mayer A.
        Detection and characterization of tumor hypoxia using pO2 histography.
        Antioxid. Redox Signal. 2007; 9: 1221-1236https://doi.org/10.1089/ars.2007.1628
        • Semenza G.L.
        Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics.
        Oncogene. 2010; 29: 625-634https://doi.org/10.1038/onc.2009.441
        • Bos R.
        • van der Groep P.
        • van der Wall E.
        • et al.
        Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma.
        Cancer. 2003; 97: 1573-1581https://doi.org/10.1002/cncr.11246
        • Zhang H.
        • Wong C.C.L.
        • Semenza G.L.
        • et al.
        HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs.
        Oncogene. 2012; 31: 1757-1770https://doi.org/10.1038/onc.2011.365
        • Gilkes D.M.
        • Chaturvedi P.
        • Semenza G.L.
        • et al.
        Collagen prolyl hydroxylases are essential for breast cancer metastasis.
        Cancer Res. 2013; 73: 3285-3296https://doi.org/10.1158/0008-5472.CAN-12-3963
        • Reiterer M.
        • Colaco R.
        • Branco C.
        • et al.
        Acute and chronic hypoxia differentially predispose lungs for metastases.
        Sci. Rep. 2019; 9: 10246https://doi.org/10.1038/s41598-019-46763-y
        • Gilkes D.M.
        • Xiang L.
        • Semenza G.L.
        • et al.
        Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells.
        Proc. Natl. Acad. Sci. U S A. 2014; 111: E384-E393https://doi.org/10.1073/pnas.1321510111
        • Kim T.H.
        • Ly C.
        • Rowat A.A.C.
        • et al.
        Stress hormone signaling through beta-adrenergic receptors regulates macrophage mechanotype and function.
        FASEB J. 2019; 33: 3997-4006https://doi.org/10.1096/fj.201801429RR
        • Kim T.H.
        • Gill N.K.
        • Rowat A.C.
        • et al.
        Cancer cells become less deformable and more invasive with activation of beta-adrenergic signaling.
        J. Cell Sci. 2016; 129: 4563-4575https://doi.org/10.1242/jcs.194803
        • Sloan E.K.
        • Priceman S.J.
        • Cole S.W.
        • et al.
        The sympathetic nervous system induces a metastatic switch in primary breast cancer.
        Cancer Res. 2010; 70: 7042-7052https://doi.org/10.1158/0008-5472.CAN-10-0522
        • Creed S.J.
        • Le C.P.
        • Sloan E.K.
        • et al.
        β2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion.
        Breast Cancer Res. 2015; 17: 145https://doi.org/10.1186/s13058-015-0655-3
        • Le C.P.
        • Nowell C.J.
        • Sloan E.K.
        • et al.
        Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination.
        Nat. Commun. 2016; 7: 10634https://doi.org/10.1038/ncomms10634
        • Northcott J.M.
        • Dean I.S.
        • Weaver V.M.
        • et al.
        Feeling stress: the mechanics of cancer progression and aggression.
        Front. Cell Dev. Biol. 2018; 6: 17https://doi.org/10.3389/fcell.2018.00017
        • Yang J.H.
        • Sakamoto H.
        • Lee R.T.
        • et al.
        Biomechanical regulation of human monocyte/macrophage molecular function.
        Am. J. Pathol. 2000; 156: 1797-1804https://doi.org/10.1016/S0002-9440(10)65051-1
        • Kalli M.
        • Li R.
        • Mills G.B.
        • Stylianopoulos T.
        • Zervantonakis I.K.
        Mechanical stress signaling in pancreatic cancer cells triggers p38 MAPK- and JNK-dependent cytoskeleton remodeling and promotes cell migration via Rac1/cdc42/myosin II.
        Mol. Cancer Res. 2021; 20: 485-497https://doi.org/10.1158/1541-7786.mcr-21-0266.MCR-21-0266
        • Levental K.R.
        • Yu H.
        • Kass L.
        • Lakins J.N.
        • Egeblad M.
        • Erler J.T.
        • Fong S.F.
        • Csiszar K.
        • Giaccia A.
        • Weninger W.
        • Yamauchi M.
        • Gasser D.L.
        • Weaver V.M.
        Matrix crosslinking forces tumor progression by enhancing integrin signaling.
        Cell. 2009; 139: 891-906https://doi.org/10.1016/j.cell.2009.10.027
        • Wyckoff J.B.
        • Jones J.G.
        • Condeelis J.S.
        • Segall J.E.
        A critical step in metastasis: in vivo analysis of intravasation at the primary tumor.
        Cancer Res. 2000; 60: 2504-2511
        • Condeelis J.
        • Pollard J.W.
        Macrophages: obligate partners for tumor cell migration, invasion, and metastasis.
        Cell. 2006; 124: 263-266https://doi.org/10.1016/j.cell.2006.01.007
        • Chen M.B.
        • Whisler J.A.
        • Jeon J.S.
        • Kamm R.D.
        Mechanisms of tumor cell extravasation in an in vitro microvascular network platform.
        Integr. Biol. (Camb). 2013; 5: 1262-1271https://doi.org/10.1039/c3ib40149a
        • Kumar S.
        • Weaver V.M.
        Mechanics, malignancy, and metastasis: the force journey of a tumor cell.
        Cancer Metastasis Rev. 2009; 28: 113-127https://doi.org/10.1007/s10555-008-9173-4
        • Yu H.
        • Mouw J.K.
        • Weaver V.M.
        Forcing form and function: biomechanical regulation of tumor evolution.
        Trends Cell Biol. 2011; 21: 47-56https://doi.org/10.1016/j.tcb.2010.08.015
        • Amos S.E.
        • Choi Y.S.
        The cancer microenvironment: mechanical challenges of the metastatic cascade.
        Front. Bioeng. Biotechnol. 2021; 9: 625859https://doi.org/10.3389/fbioe.2021.625859
        • Riehl B.D.
        • Kim E.
        • Lim J.Y.
        • et al.
        The role of microenvironmental cues and mechanical loading milieus in breast cancer cell progression and metastasis.
        Front. Bioeng. Biotechnol. 2021; 8: 608526https://doi.org/10.3389/fbioe.2020.608526
        • Das J.
        • Chakraborty S.
        • Maiti T.K.
        Mechanical stress-induced autophagic response: a cancer-enabling characteristic?.
        Semin. Cancer Biol. 2020; 66: 101-109https://doi.org/10.1016/j.semcancer.2019.05.017
        • Swaminathan V.
        • Mythreye K.
        • Superfine R.
        • et al.
        Mechanical stiffness grades metastatic potential in patient tumor cells and in cancer cell lines.
        Cancer Res. 2011; 71: 5075-5080https://doi.org/10.1158/0008-5472.can-11-0247
        • Liu C.
        • Pei H.
        • Tan F.
        Matrix stiffness and colorectal cancer.
        Onco Targets Ther. 2020; 13: 2747-2755https://doi.org/10.2147/OTT.S231010
        • Jain R.K.
        • Martin J.D.
        • Stylianopoulos T.
        The role of mechanical forces in tumor growth and therapy.
        Annu. Rev. Biomed. Eng. 2014; 16: 321-346https://doi.org/10.1146/annurev-bioeng-071813-105259
        • Chaudhuri O.
        • Koshy S.T.
        • Mooney D.J.
        • et al.
        Extracellular matrix stiffness and composition jointly regulate the induction of malignant phenotypes in mammary epithelium.
        Nat. Mater. 2014; 13: 970-978https://doi.org/10.1038/nmat4009
        • Peela N.
        • Sam F.S.
        • Nikkhah M.
        • et al.
        A three dimensional micropatterned tumor model for breast cancer cell migration studies.
        Biomaterials. 2016; 81: 72-83https://doi.org/10.1016/j.biomaterials.2015.11.039
        • Baker A.M.
        • Bird D.
        • Erler J.T.
        • et al.
        Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK.
        Oncogene. 2013; 32: 1863-1868https://doi.org/10.1038/onc.2012.202
        • Kim Y.
        • Roh S.
        • Kim J.C.
        • et al.
        Differential expression of the LOX family genes in human colorectal adenocarcinomas.
        Oncol. Rep. 2009; 22: 799-804https://doi.org/10.3892/or_00000502
        • Krndija D.
        • Schmid H.
        • von Wichert G.
        • et al.
        Substrate stiffness and the receptor-type tyrosine-protein phosphatase alpha regulate spreading of colon cancer cells through cytoskeletal contractility.
        Oncogene. 2010; 29: 2724-2738https://doi.org/10.1038/onc.2010.25
        • Ulrich T.A.
        • de Juan Pardo E.M.
        • Kumar S.
        The mechanical rigidity of the extracellular matrix regulates the structure, motility, and proliferation of glioma cells.
        Cancer Res. 2009; 69: 4167-4174https://doi.org/10.1158/0008-5472.CAN-08-4859
        • Rice A.J.
        • Cortes E.
        • Del Rio Hernandez A.
        • et al.
        Matrix stiffness induces epithelial-mesenchymal transition and promotes chemoresistance in pancreatic cancer cells.
        Oncogenesis. 2017; 6: e352https://doi.org/10.1038/oncsis.2017.54
        • Nukuda A.
        • Sasaki C.
        • Haga H.
        • et al.
        Stiff substrates increase YAP-signaling-mediated matrix metalloproteinase-7 expression.
        Oncogenesis. 2015; 4: e165https://doi.org/10.1038/oncsis.2015.24
        • Lee J.Y.
        • Chang J.K.
        • Chaudhuri O.
        • et al.
        YAP-independent mechanotransduction drives breast cancer progression.
        Nat. Commun. 2019; 10: 1848https://doi.org/10.1038/s41467-019-09755-0
        • Peng Y.
        • Chen Z.
        • Liu Y.
        • et al.
        ROCK isoforms differentially modulate cancer cell motility by mechanosensing the substrate stiffness.
        Acta Biomater. 2019; 88: 86-101https://doi.org/10.1016/j.actbio.2019.02.015
        • Pang M.
        • Teng Y.
        • Xiong C.
        • et al.
        Substrate stiffness promotes latent TGF-β1 activation in hepatocellular carcinoma.
        Biochem. Biophys. Res. Commun. 2017; 483: 553-558https://doi.org/10.1016/j.bbrc.2016.12.107
        • Lin F.
        • Zhang H.
        • Xiong C.
        • et al.
        Substrate stiffness coupling TGF-β1 modulates migration and traction force of MDA-MB-231 human breast cancer cells in vitro.
        Acs Biomater. Sci. Eng. 2018; 4: 1337-1345https://doi.org/10.1021/acsbiomaterials.7b00835
        • Tang K.
        • Li S.
        • Liu Y.
        • et al.
        Shear stress stimulates integrin β1 trafficking and increases directional migration of cancer cells via promoting deacetylation of microtubules.
        Biochim. Biophys. Acta Mol. Cell Res. 2020; 1867: 118676https://doi.org/10.1016/j.bbamcr.2020.118676
        • Holle A.W.
        • Govindan Kutty Devi N.
        • Spatz J.P.
        • et al.
        Cancer cells invade confined microchannels via a self-directed mesenchymal-to-amoeboid transition.
        Nano Lett. 2019; 19: 2280-2290https://doi.org/10.1021/acs.nanolett.8b04720
        • Laakkonen P.
        • Waltari M.
        • Alitalo K.
        • et al.
        Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth.
        Cancer Res. 2007; 67: 593-599https://doi.org/10.1158/0008-5472.can-06-3567
        • Maimari N.
        • Pedrigi R.M.
        • Krams R.
        • et al.
        Integration of flow studies for robust selection of mechanoresponsive genes.
        Thromb. Haemost. 2016; 115: 474-483https://doi.org/10.1160/TH15-09-0704
        • Follain G.
        • Osmani N.
        • Goetz J.G.
        • et al.
        Hemodynamic forces tune the arrest, adhesion, and extravasation of circulating tumor cells.
        Dev. Cell. 2018; 45: 33-52.e12https://doi.org/10.1016/j.devcel.2018.02.015
        • Headley M.B.
        • Bins A.
        • Krummel M.F.
        • et al.
        Visualization of immediate immune responses to pioneer metastatic cells in the lung.
        Nature. 2016; 531: 513-517https://doi.org/10.1038/nature16985
        • Rizvi I.
        • Gurkan U.A.
        • Hasan T.
        • et al.
        Flow induces epithelial-mesenchymal transition, cellular heterogeneity and biomarker modulation in 3D ovarian cancer nodules.
        Proc. Natl. Acad. Sci. U S A. 2013; 110: E1974-E1983https://doi.org/10.1073/pnas.1216989110
        • Cornelison R.C.
        • Brennan C.E.
        • Munson J.M.
        • et al.
        Convective forces increase CXCR4-dependent glioblastoma cell invasion in GL261 murine model.
        Sci. Rep. 2018; 8: 17057https://doi.org/10.1038/s41598-018-35141-9
        • Streitberger K.J.
        • Lilaj L.
        • Sack I.
        • et al.
        How tissue fluidity influences brain tumor progression.
        P Natl. Acad. Sci. U S A. 2020; 117: 128-134https://doi.org/10.1073/pnas.1913511116
        • Paszek M.J.
        • Zahir N.
        • Weaver V.M.
        • et al.
        Tensional homeostasis and the malignant phenotype.
        Cancer Cell. 2005; 8: 241-254https://doi.org/10.1016/j.ccr.2005.08.010
        • Ondeck M.G.
        • Kumar A.
        • Engler A.J.
        • et al.
        Dynamically stiffened matrix promotes malignant transformation of mammary epithelial cells via collective mechanical signaling.
        Proc. Natl. Acad. Sci. U S A. 2019; 116: 3502-3507https://doi.org/10.1073/pnas.1814204116
        • Wullkopf L.
        • West A.K.V.
        • Erler J.T.
        • et al.
        Cancer cells' ability to mechanically adjust to extracellular matrix stiffness correlates with their invasive potential.
        Mol. Biol. Cell. 2018; 29: 2378-2385https://doi.org/10.1091/mbc.E18-05-0319
        • Cox T.R.
        • Erler J.T.
        Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer.
        Dis. Model. Mech. 2011; 4: 165-178https://doi.org/10.1242/dmm.004077
        • Provenzano P.P.
        • Inman D.R.
        • Keely P.J.
        • et al.
        Mammary epithelial-specific disruption of focal adhesion kinase retards tumor formation and metastasis in a transgenic mouse model of human breast cancer.
        Am. J. Pathol. 2008; 173: 1551-1565https://doi.org/10.2353/ajpath.2008.080308
        • Lu P.
        • Weaver V.M.
        • Werb Z.
        The extracellular matrix: a dynamic niche in cancer progression.
        J. Cell Biol. 2012; 196: 395-406https://doi.org/10.1083/jcb.201102147
        • Nissen N.I.
        • Karsdal M.
        • Willumsen N.
        Collagens and Cancer associated fibroblasts in the reactive stroma and its relation to Cancer biology.
        J. Exp. Clin. Cancer Res. 2019; 38: 115https://doi.org/10.1186/s13046-019-1110-6
        • Jiang H.
        • Torphy R.J.
        • Collisson E.A.
        • et al.
        Pancreatic ductal adenocarcinoma progression is restrained by stromal matrix.
        J. Clin. Invest. 2020; 130: 4704-4709https://doi.org/10.1172/JCI136760
        • Nguyen A.V.
        • Nyberg K.D.
        • Rowat A.C.
        • et al.
        Stiffness of pancreatic cancer cells is associated with increased invasive potential.
        Integr. Biol. 2016; 8: 1232-1245https://doi.org/10.1039/c6ib00135a
        • Guck J.
        • Schinkinger S.
        • Bilby C.
        • et al.
        Optical deformability as an inherent cell marker for testing malignant transformation and metastatic competence.
        Biophys. J. 2005; 88: 3689-3698https://doi.org/10.1529/biophysj.104.045476
        • Cross S.E.
        • Jin Y.S.
        • Gimzewski J.K.
        • et al.
        Nanomechanical analysis of cells from cancer patients.
        Nat. Nanotechnol. 2007; 2: 780-783https://doi.org/10.1038/nnano.2007.388
        • Liu Y.
        • Zhang T.
        • Huang B.
        • et al.
        Cell softness prevents cytolytic T-cell killing of tumor-repopulating cells.
        Cancer Res. 2021; 81: 476-488https://doi.org/10.1158/0008-5472.CAN-20-2569
        • Lv J.
        • Liu Y.
        • Huang B.
        • et al.
        Cell softness regulates tumorigenicity and stemness of cancer cells.
        EMBO J. 2021; 40: e106123https://doi.org/10.15252/embj.2020106123
        • Xu W.
        • Mezencev R.
        • Sulchek T.
        • et al.
        Cell stiffness is a biomarker of the metastatic potential of ovarian cancer cells.
        PLoS One. 2012; 7: e46609https://doi.org/10.1371/journal.pone.0046609
        • Yu H.W.
        • Chen Y.
        • Kuo J.C.
        • et al.
        β- PIX controls intracellular viscoelasticity to regulate lung cancer cell migration.
        J. Cell Mol. Med. 2015; 19: 934-947https://doi.org/10.1111/jcmm.12441
        • Schiffhauer E.S.
        • Luo T.
        • Robinson D.N.
        • et al.
        Mechanoaccumulative elements of the mammalian actin cytoskeleton.
        Curr. Biol. 2016; 26: 1473-1479https://doi.org/10.1016/j.cub.2016.04.007
        • Kothari P.
        • Johnson C.
        • Robinson D.N.
        • et al.
        How the mechanobiome drives cell behavior, viewed through the lens of control theory.
        J. Cell Sci. 2019; 132: jcs234476https://doi.org/10.1242/jcs.234476
        • Halder D.
        • Mallick D.
        • Jana S.S.
        • et al.
        Nonmuscle Myosin II in cancer cell migration and mechanotransduction.
        Int. J. Biochem. Cell Biol. 2021; 139: 106058https://doi.org/10.1016/j.biocel.2021.106058
        • Bryan D.S.
        • Stack M.
        • Weichselbaum R.R.
        • et al.
        4-Hydroxyacetophenone modulates the actomyosin cytoskeleton to reduce metastasis.
        Proc. Natl. Acad. Sci. U S A. 2020; 117: 22423-22429https://doi.org/10.1073/pnas.2014639117
        • Peng Y.
        • Chen Z.
        • Liu Y.
        • et al.
        Non-muscle myosin II isoforms orchestrate substrate stiffness sensing to promote cancer cell contractility and migration.
        Cancer Lett. 2022; 524: 245-258https://doi.org/10.1016/j.canlet.2021.10.030
        • Huang Q.
        • Li X.
        • Lin J.
        • et al.
        ACTN4 promotes the proliferation, migration, metastasis of osteosarcoma and enhances its invasive ability through the NF-κB pathway.
        Pathol. Oncol. Res. 2020; 26: 893-904https://doi.org/10.1007/s12253-019-00637-w
        • Ma X.
        • Xue H.
        • Zuo Y.
        • et al.
        Serum actinin-4 levels as a potential diagnostic and prognostic marker in cervical cancer.
        Dis. Markers. 2020; 2020: 5327378https://doi.org/10.1155/2020/5327378
        • Jung J.
        • Kim S.
        • Ko J.
        • et al.
        α-Actinin-4 regulates cancer stem cell properties and chemoresistance in cervical cancer.
        Carcinogenesis. 2020; 41: 940-949https://doi.org/10.1093/carcin/bgz168
        • Barai A.
        • Mukherjee A.
        • Sen S.
        • et al.
        α-Actinin-4 drives invasiveness by regulating myosin IIB expression and myosin IIA localization.
        J. Cell Sci. 2021; 134: jcs258581https://doi.org/10.1242/jcs.258581
        • Burton K.M.
        • Cao H.
        • Razidlo G.L.
        • et al.
        Dynamin 2 interacts with alpha-actinin 4 to drive tumor cell invasion.
        Mol. Biol. Cell. 2020; 31: 439-451https://doi.org/10.1091/mbc.E19-07-0395
        • Wang K.
        • Singer S.J.
        Interaction of filamin with f-actin in solution.
        Proc. Natl. Acad. Sci. U S A. 1977; 74: 2021-2025https://doi.org/10.1073/pnas.74.5.2021
        • Stossel T.P.
        • Condeelis J.
        • Shapiro S.S.
        • et al.
        Filamins as integrators of cell mechanics and signalling.
        Nat. Rev. Mol. Cell Biol. 2001; 2: 138-145https://doi.org/10.1038/35052082
        • Feng Y.
        • Walsh C.A.
        The many faces of filamin: a versatile molecular scaffold for cell motility and signalling.
        Nat. Cell Biol. 2004; 6: 1034-1038https://doi.org/10.1038/ncb1104-1034
        • Glogauer M.
        • Arora P.
        • McCulloch C.A.
        • et al.
        The role of actin-binding protein 280 in integrin-dependent mechanoprotection.
        J. Biol. Chem. 1998; 273: 1689-1698https://doi.org/10.1074/jbc.273.3.1689
        • Ma H.R.
        • Cao L.
        • Qian Z.
        • et al.
        Filamin B extensively regulates transcription and alternative splicing, and is associated with apoptosis in HeLa cells.
        Oncol. Rep. 2020; 43: 1536-1546https://doi.org/10.3892/or.2020.7532
        • Yesilkaya F.
        • Tastekin D.
        • Pence S.
        • et al.
        Examination of the expression levels of MACC1, Filamin A and FBXW7 genes in colorectal cancer patients.
        North. Clin. Istanb. 2019; 7: 1-5https://doi.org/10.14744/nci.2019.26780
        • Cheng L.
        • Tong Q.
        Interaction of FLNA and ANXA2 promotes gefitinib resistance by activating the Wnt pathway in non-small-cell lung cancer.
        Mol. Cell Biochem. 2021; 476: 3563-3575https://doi.org/10.1007/s11010-021-04179-1
        • Patarat R.
        • Riku S.
        • Puttipanyalears C.
        • et al.
        The expression of FLNA and CLU in PBMCs as a novel screening marker for hepatocellular carcinoma.
        Sci. Rep. 2021; 11: 14838https://doi.org/10.1038/s41598-021-94330-1
        • Ramachandran R.
        • Schmid S.L.
        The dynamin superfamily.
        Curr. Biol. 2018; 28: R411-R416https://doi.org/10.1016/j.cub.2017.12.013
        • Jimah J.R.
        • Hinshaw J.E.
        Structural insights into the mechanism of dynamin superfamily proteins.
        Trends Cell Biol. 2019; 29: 257-273https://doi.org/10.1016/j.tcb.2018.11.003
        • Tian M.
        • Yang X.
        • Guo S.
        • et al.
        The expression of dynamin 1, 2, and 3 in human hepatocellular carcinoma and patient prognosis.
        Med. Sci. Monit. 2020; 26: e923359https://doi.org/10.12659/MSM.923359
        • von Beek C.
        • Alriksson L.
        • Pejler G.
        • et al.
        Dynamin inhibition causes context-dependent cell death of leukemia and lymphoma cells.
        PLoS One. 2021; 16: e0256708https://doi.org/10.1371/journal.pone.0256708
        • Zhang R.
        • Lee D.M.
        • Chen E.H.
        • et al.
        Dynamin regulates the dynamics and mechanical strength of the actin cytoskeleton as a multifilament actin-bundling protein.
        Nat. Cell Biol. 2020; 22: 674-688https://doi.org/10.1038/s41556-020-0519-7
        • Gu C.
        • Yaddanapudi S.
        • Sever S.
        • et al.
        Direct dynamin-actin interactions regulate the actin cytoskeleton.
        EMBO J. 2010; 29: 3593-3606https://doi.org/10.1038/emboj.2010.249
        • Wang Z.
        • Zhu Z.
        • Sun S.
        • et al.
        NMIIA promotes tumorigenesis and prevents chemosensitivity in colorectal cancer by activating AMPK/mTOR pathway.
        Exp. Cell Res. 2021; 398: 112387https://doi.org/10.1016/j.yexcr.2020.112387
        • Pecci A.
        • Ma X.
        • Adelstein R.S.
        • et al.
        MYH9: structure, functions and role of non-muscle myosin IIA in human disease.
        Gene. 2018; 664: 152-167https://doi.org/10.1016/j.gene.2018.04.048
        • Honda K.
        The biological role of actinin-4 (ACTN4) in malignant phenotypes of cancer.
        Cell Biosci. 2015; 5: 41https://doi.org/10.1186/s13578-015-0031-0
        • Park S.
        • Kang M.
        • Ko J.
        • et al.
        α-Actinin-4 promotes the progression of prostate cancer through the Akt/GSK-3β/β-catenin signaling pathway.
        Front. Cell Dev Biol. 2020; 8: 588544https://doi.org/10.3389/fcell.2020.588544
        • Liu X.
        • Chu K.M.
        α-Actinin-4 promotes metastasis in gastric cancer.
        Lab. Invest. 2017; 97: 1084-1094https://doi.org/10.1038/labinvest.2017.28
        • Kamil M.
        • Shinsato Y.
        • Arita K.
        • et al.
        High filamin-C expression predicts enhanced invasiveness and poor outcome in glioblastoma multiforme.
        Br. J. Cancer. 2019; 120: 819-826https://doi.org/10.1038/s41416-019-0413-x
        • Yamaguchi H.
        • Condeelis J.
        Regulation of the actin cytoskeleton in cancer cell migration and invasion.
        Biochim. Biophys. Acta. 2007; 1773: 642-652https://doi.org/10.1016/j.bbamcr.2006.07.001
        • Foerster F.
        • Braig S.
        • Vollmar A.M.
        • et al.
        Targeting the actin cytoskeleton: selective antitumor action via trapping PKCɛ.
        Cell Death Dis. 2014; 5: e1398https://doi.org/10.1038/cddis.2014.363
        • Hsu K.S.
        • Kao H.Y.
        Alpha-actinin 4 and tumorigenesis of breast cancer.
        Vitam Horm. 2013; 93: 323-351https://doi.org/10.1016/B978-0-12-416673-8.00005-8
        • Park J.S.
        • Burckhardt C.J.
        • Danuser G.
        • et al.
        Mechanical regulation of glycolysis via cytoskeleton architecture.
        Nature. 2020; 578: 621-626https://doi.org/10.1038/s41586-020-1998-1
        • Ong M.S.
        • Deng S.
        • Yap C.T.
        • et al.
        Cytoskeletal proteins in cancer and intracellular stress: a therapeutic perspective.
        Cancers. 2020; 12https://doi.org/10.3390/cancers12010238
        • DeWane G.
        • Salvi A.M.
        • DeMali K.A.
        Fueling the cytoskeleton - links between cell metabolism and actin remodeling.
        J. Cell Sci. 2021; 134: jcs248385https://doi.org/10.1242/jcs.248385
        • Angstadt S.
        • Zhu Q.
        • Anders R.A.
        • et al.
        Pancreatic ductal adenocarcinoma cortical mechanics and clinical implications.
        Front. Oncol. 2022; 12: 809179https://doi.org/10.3389/fonc.2022.809179
        • Fife C.M.
        • McCarroll J.A.
        • Kavallaris M.
        Movers and shakers: cell cytoskeleton in cancer metastasis.
        Br. J. Pharmacol. 2014; 171: 5507-5523https://doi.org/10.1111/bph.12704
        • Etienne-Manneville S.
        Actin and microtubules in cell motility: which one is in control?.
        Traffic. 2004; 5: 470-477https://doi.org/10.1111/j.1600-0854.2004.00196.x
        • Blanchoin L.
        • Boujemaa-Paterski R.
        • Plastino J.
        • et al.
        Actin dynamics, architecture, and mechanics in cell motility.
        Physiol. Rev. 2014; 94: 235-263https://doi.org/10.1152/physrev.00018.2013
        • Picariello H.S.
        • Kenchappa R.S.
        • Rosenfeld S.S.
        • et al.
        Myosin IIA suppresses glioblastoma development in a mechanically sensitive manner.
        Proc. Natl. Acad. Sci. U S A. 2019; 116: 15550-15559https://doi.org/10.1073/pnas.1902847116
        • Bai H.
        • Zhu Q.
        • Anders R.A.
        • et al.
        Yes-associated protein impacts adherens junction assembly through regulating actin cytoskeleton organization.
        Am. J. Physiol. Gastrointest. Liver Physiol. 2016; 311: G396-G411https://doi.org/10.1152/ajpgi.00027.2016
        • Yu Q.
        • Zhang B.
        • Liu Y.
        • et al.
        Actin cytoskeleton-disrupting and magnetic field-responsive multivalent supramolecular assemblies for efficient cancer therapy.
        ACS Appl. Mater. Inter. 2020; 12: 13709-13717https://doi.org/10.1021/acsami.0c01762
        • Al Absi A.
        • Wurzer H.
        • Thomas C.
        • et al.
        Actin cytoskeleton remodeling drives breast cancer cell escape from natural killer-mediated cytotoxicity.
        Cancer Res. 2018; 78: 5631-5643https://doi.org/10.1158/0008-5472.CAN-18-0441
        • Ayad N.M.E.
        • Weaver V.M.
        Tension in tumour cells keeps metabolism high.
        Nature. 2020; 578: 517-518https://doi.org/10.1038/d41586-020-00314-y
        • Liberti M.V.
        • Locasale J.W.
        The Warburg effect: how does it benefit cancer cells?.
        Trends Biochem. Sci. 2016; 41: 211-218https://doi.org/10.1016/j.tibs.2016.01.004
        • Ouderkirk J.L.
        • Krendel M.
        Non-muscle myosins in tumor progression, cancer cell invasion, and metastasis.
        Cytoskeleton. 2014; 71: 447-463https://doi.org/10.1002/cm.21187
        • Vicente-Manzanares M.
        • Ma X.
        • Horwitz A.R.
        • et al.
        Non-muscle myosin II takes centre stage in cell adhesion and migration.
        Nat. Rev. Mol. Cell Biol. 2009; 10: 778-790https://doi.org/10.1038/nrm2786
        • Chin V.T.
        • Nagrial A.M.
        • Pajic M.
        • et al.
        Rho-associated kinase signalling and the cancer microenvironment: novel biological implications and therapeutic opportunities.
        Expert Rev. Mol. Med. 2015; 17: e17https://doi.org/10.1017/erm.2015.17
        • Schramek D.
        • Sendoel A.
        • Fuchs E.
        • et al.
        Direct in vivo RNAi screen unveils myosin IIa as a tumor suppressor of squamous cell carcinomas.
        Science. 2014; 343: 309-313https://doi.org/10.1126/science.1248627
        • Anne Conti M.
        • Saleh A.D.
        • Adelstein R.S.
        • et al.
        Conditional deletion of nonmuscle myosin II-A in mouse tongue epithelium results in squamous cell carcinoma.
        Sci. Rep. 2015; 5: 14068https://doi.org/10.1038/srep14068
        • Nguyen L.T.S.
        • Robinson D.N.
        The unusual suspects in cytokinesis: fitting the pieces together.
        Front. Cell Dev Biol. 2020; 8: 441https://doi.org/10.3389/fcell.2020.00441
        • Ren Y.
        • West-Foyle H.
        • Robinson D.N.
        • et al.
        Genetic suppression of a phosphomimic myosin II identifies system-level factors that promote myosin II cleavage furrow accumulation.
        Mol. Biol. Cell. 2014; 25: 4150-4165https://doi.org/10.1091/mbc.e14-08-1322
        • Kothari P.
        • Srivastava V.
        • Robinson D.N.
        • et al.
        Contractility kits promote assembly of the mechanoresponsive cytoskeletal network.
        J. Cell Sci. 2019; 132: jcs226704https://doi.org/10.1242/jcs.226704
        • Wang Y.
        • Liu S.
        • Yang J.
        • et al.
        Myosin heavy chain 9: oncogene or tumor suppressor gene?.
        Med. Sci. Monit. 2019; 25: 888-892https://doi.org/10.12659/MSM.912320
        • Ivkovic S.
        • Beadle C.
        • Rosenfeld S.S.
        • et al.
        Direct inhibition of myosin II effectively blocks glioma invasion in the presence of multiple motogens.
        Mol. Biol. Cell. 2012; 23: 533-542https://doi.org/10.1091/mbc.E11-01-0039
        • Beadle C.
        • Assanah M.C.
        • Canoll P.
        • et al.
        The role of myosin II in glioma invasion of the brain.
        Mol. Biol. Cell. 2008; 19: 3357-3368https://doi.org/10.1091/mbc.E08-03-0319
        • Singh A.
        • Settleman J.
        Oncogenic K-ras "addiction" and synthetic lethality.
        Cell Cycle. 2009; 8: 2676-2678https://doi.org/10.4161/cc.8.17.9336
        • Suissa S.
        • Azoulay L.
        Metformin and cancer: mounting evidence against an association.
        Diabetes Care. 2014; 37: 1786-1788https://doi.org/10.2337/dc14-0500
        • Wheaton W.W.
        • Weinberg S.E.
        • Chandel N.S.
        • et al.
        Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis.
        Elife. 2014; 3: e02242https://doi.org/10.7554/eLife.02242
        • Podhorecka M.
        • Ibanez B.
        • Dmoszynska A.
        Metformin - its potential anti-cancer and anti-aging effects.
        Postep Hig Med. Dosw. 2017; 71: 170-175https://doi.org/10.5604/01.3001.0010.3801
        • Song Z.
        • Wei B.
        • Chen L.
        • et al.
        Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells.
        Mol. Med. Rep. 2017; 15: 1909-1915https://doi.org/10.3892/mmr.2017.6205
        • Whitburn J.
        • Edwards C.M.
        • Sooriakumaran P.
        Metformin and prostate cancer: a new role for an old drug.
        Curr. Urol. Rep. 2017; 18: 46https://doi.org/10.1007/s11934-017-0693-8
        • Chen G.X.
        • Yu C.
        • Zhang S.Y.
        • et al.
        Metformin suppresses gastric cancer progression through calmodulin-like protein 3 secreted from tumor-associated fibroblasts.
        Oncol. Rep. 2019; 41: 405-414https://doi.org/10.3892/or.2018.6783
        • Kopf-Maier P.
        • Muhlhausen S.K.
        Changes in the cytoskeleton pattern of tumor cells by cisplatin in vitro.
        Chem. Biol. Interact. 1992; 82: 295-316https://doi.org/10.1016/0009-2797(92)90002-3
        • Kung M.L.
        • Hsieh C.W.
        • Hsieh S.
        • et al.
        Nanoscale characterization illustrates the cisplatin-mediated biomechanical changes of B16-F10 melanoma cells.
        Phys. Chem. Chem. Phys. 2016; 18: 7124-7131https://doi.org/10.1039/c5cp07971c
        • Raudenska M.
        • Kratochvilova M.
        • Masarik M.
        • et al.
        Cisplatin enhances cell stiffness and decreases invasiveness rate in prostate cancer cells by actin accumulation.
        Sci. Rep. 2019; 9: 1660https://doi.org/10.1038/s41598-018-38199-7
        • Vassilopoulos A.
        • Xiao C.
        • Deng C.X.
        • et al.
        Synergistic therapeutic effect of cisplatin and phosphatidylinositol 3-kinase (PI3K) inhibitors in cancer growth and metastasis of Brca1 mutant tumors.
        J. Biol. Chem. 2014; 289: 24202-24214https://doi.org/10.1074/jbc.M114.567552
        • Kalender M.E.
        • Demiryurek S.
        • Camci C.
        • et al.
        Association between the Thr431Asn polymorphism of the ROCK2 gene and risk of developing metastases of breast cancer.
        Oncol. Res. 2009; 18: 583-591https://doi.org/10.3727/096504010x12767359113767
        • Kamai T.
        • Tsujii T.
        • Oshima H.
        • et al.
        Significant association of Rho/ROCK pathway with invasion and metastasis of bladder cancer.
        Clin. Cancer Res. 2003; 9: 2632-2641
        • Lane J.
        • Martin T.A.
        • Jiang W.G.
        • et al.
        The expression and prognostic value of ROCK I and ROCK II and their role in human breast cancer.
        Int. J. Oncol. 2008; 33: 585-593
        • Liu S.
        • Goldstein R.H.
        • Rosenblatt M.
        • et al.
        Inhibition of rho-associated kinase signaling prevents breast cancer metastasis to human bone.
        Cancer Res. 2009; 69: 8742-8751https://doi.org/10.1158/0008-5472.CAN-09-1541
        • Miyamoto C.
        • Maehata Y.
        • Lee M.C.i.
        • et al.
        Fasudil suppresses fibrosarcoma growth by stimulating secretion of the chemokine CXCL14/BRAK.
        J. Pharmacol. Sci. 2012; 120: 241-249https://doi.org/10.1254/jphs.12177fp
        • Guerra F.S.
        • Oliveira R.G.d.
        • Fernandes P.D.
        • et al.
        ROCK inhibition with Fasudil induces beta-catenin nuclear translocation and inhibits cell migration of MDA-MB 231 human breast cancer cells.
        Sci. Rep. 2017; 7: 13723https://doi.org/10.1038/s41598-017-14216-z
        • Xia Y.
        • Cai X.Y.
        • Wu G.
        • et al.
        Rho kinase inhibitor Fasudil suppresses the vasculogenic mimicry of B16 mouse melanoma cells both in vitro and in vivo.
        Mol. Cancer Ther. 2015; 14: 1582-1590https://doi.org/10.1158/1535-7163.MCT-14-0523
        • Lee M.H.
        • Kundu J.K.
        • Shim J.H.
        • et al.
        Targeting ROCK/LIMK/cofilin signaling pathway in cancer.
        Arch. Pharm. Res. 2019; 42: 481-491https://doi.org/10.1007/s12272-019-01153-w
        • Vennin C.
        • Chin V.T.
        • Timpson P.
        • et al.
        Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis.
        Sci. Transl Med. 2017; 9: eaai8504https://doi.org/10.1126/scitranslmed.aai8504
        • Cascione M.
        • De Matteis V.
        • Rinaldi R.
        • et al.
        Morphomechanical and structural changes induced by ROCK inhibitor in breast cancer cells.
        Exp. Cell Res. 2017; 360: 303-309https://doi.org/10.1016/j.yexcr.2017.09.020
        • Jiang L.
        • Wen J.
        • Luo W.
        Rhoassociated kinase inhibitor, Y27632, inhibits the invasion and proliferation of T24 and 5367 bladder cancer cells.
        Mol. Med. Rep. 2015; 12: 7526-7530https://doi.org/10.3892/mmr.2015.4404
        • Li Y.
        • Li X.
        • Zhu Y.
        • et al.
        Visfatin derived from ascites promotes ovarian cancer cell migration through Rho/ROCK signaling-mediated actin polymerization.
        Eur. J. Cancer Prev. 2015; 24: 231-239https://doi.org/10.1097/CEJ.0000000000000064
        • Routhier A.
        • Astuccio M.
        • Bryan B.
        • et al.
        Pharmacological inhibition of Rho-kinase signaling with Y-27632 blocks melanoma tumor growth.
        Oncol. Rep. 2010; 23: 861-867