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Differential Contributions of Actin and Myosin to the Physical Phenotypes and Invasion of Pancreatic Cancer Cells

  • Angelyn V. Nguyen
  • Brittany Trompetto
  • Xing Haw Marvin Tan
  • Michael B. Scott
  • Kenneth Hsueh-heng Hu
  • Eric Deeds
  • Manish J. Butte
  • Pei Yu Chiou
  • Amy C. RowatEmail author
Original Article
  • 75 Downloads

Abstract

Introduction

Metastasis is a fundamentally physical process in which cells deform through narrow gaps and generate forces to invade surrounding tissues. While it is commonly thought that increased cell deformability is an advantage for invading cells, we previously found that more invasive pancreatic ductal adenocarcinoma (PDAC) cells are stiffer than less invasive PDAC cells. Here we investigate potential mechanisms of the simultaneous increase in PDAC cell stiffness and invasion, focusing on the contributions of myosin II, Arp2/3, and formins.

Method

We measure cell invasion using a 3D scratch wound invasion assay and cell stiffness using atomic force microscopy (AFM). To determine the effects of actin- and myosin-mediated force generation on cell stiffness and invasion, we treat cells with pharmacologic inhibitors of myosin II (blebbistatin), Arp2/3 (CK-666), and formins (SMIFH2).

Results

We find that the activity of myosin II, Arp2/3, and formins all contribute to the stiffness of PDAC cells. Interestingly, we find that the invasion of PDAC cell lines is differentially affected when the activity of myosin II, Arp2/3, or formins is inhibited, suggesting that despite having similar tissue origins, different PDAC cell lines may rely on different mechanisms for invasion.

Conclusions

These findings deepen our knowledge of the factors that regulate cancer cell mechanotype and invasion, and incite further studies to develop therapeutics that target multiple mechanisms of invasion for improved clinical benefit.

Keywords

Mechanobiology Cytoskeleton Pancreatic ductal adenocarcinoma Cell stiffness Arp2/3 Formins Traction forces Cell motility 

Notes

Acknowledgments

We thank our funding sources: the National Science Foundation (CAREER DBI-1254185 and BMMB-1906165 to ACR), the Farber Family Foundation, and UCLA Integrative Biology & Physiology Eureka Scholarship (to AVN), and the National Institutes of Health (R01 GM110482 to MJB). We would also like to thank Timothy Donahue and his laboratory for their insights into PDAC, as well as their generous contributions of the PDAC cell lines used in our studies. We are also grateful to Gordon Robertson and Ewan Gibb for their bioinformatics expertise. The MMP activity assay was performed in the UCLA Molecular Shared Screening Resource in the California NanoSystems Institute with technical support from Robert Damoiseaux and Bobby Tofig.

Conflict of interest

Angelyn V. Nguyen, Brittany Trompetto, Xing Haw Marvin Tan, Michael B. Scott, Kenneth Hsueh-heng Hu, Eric Deeds, Manish J. Butte, Pei Yu Chiou, and Amy C. Rowat have no conflicts of interest.

Ethical standards

No human or animals studies were carried out by the authors for this article.

Supplementary material

12195_2019_603_MOESM1_ESM.pdf (342 kb)
Electronic supplementary material 1 (PDF 342 kb)

References

  1. 1.
    Ali, M. H., D. P. Pearlstein, C. E. Mathieu, P. T. Schumacker, H. Mir, and T. Paul. Mitochondrial requirement for endothelial responses to cyclic strain: implications for mechanotransduction. Am. J. Physiol. Lung Cell. Mol. Physiol. 60637:486–496, 2004.CrossRefGoogle Scholar
  2. 2.
    Arjonen, A., et al. Mutant p53–associated myosin-X upregulation promotes breast cancer invasion and metastasis. J. Clin. Invest. 124:1069–1082, 2014.CrossRefGoogle Scholar
  3. 3.
    Barretina, J., et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483:603–607, 2012.CrossRefGoogle Scholar
  4. 4.
    Beadle, C., M. C. Assanah, P. Monzo, R. Vallee, S. S. Rosenfeld, and P. Canoll. The role of myosin II in glioma invasion of the brain. Mol. Biol. Cell 19:3357–3368, 2008.CrossRefGoogle Scholar
  5. 5.
    Bieling, P., et al. Force feedback controls motor activity and mechanical properties of self-assembling branched actin networks. Cell 164:115–127, 2016.CrossRefGoogle Scholar
  6. 6.
    Bronte, G., et al. Driver mutations and differential sensitivity to targeted therapies: a new approach to the treatment of lung adenocarcinoma. Cancer Treat. Rev. 36(Suppl 3):S21–S29, 2010.CrossRefGoogle Scholar
  7. 7.
    Burridge, K., and C. Guilluy. Focal adhesions, stress fibers and mechanical tension. Exp. Cell Res. 343:14–20, 2016.CrossRefGoogle Scholar
  8. 8.
    Calzado-Martín, A., M. Encinar, J. Tamayo, M. Calleja, and A. San Paulo. Effect of actin organization on the stiffness of living breast cancer cells revealed by peak-force modulation atomic force microscopy. ACS Nano 10:3365–3374, 2016.CrossRefGoogle Scholar
  9. 9.
    Cartagena-Rivera, A. X., J. S. Logue, C. M. Waterman, and R. S. Chadwick. Actomyosin cortical mechanical properties in nonadherent cells determined by atomic force microscopy. Biophys. J. 110:2528–2539, 2016.CrossRefGoogle Scholar
  10. 10.
    Chan, C. J., et al. Myosin II activity softens cells in suspension. Biophys. J. 108:1856–1869, 2015.CrossRefGoogle Scholar
  11. 11.
    Chan, C. K., et al. Tumour-suppressor microRNAs regulate ovarian cancer cell physical properties and invasive behaviour. Open Biol. 6:160275, 2016.CrossRefGoogle Scholar
  12. 12.
    Chang, D. Z. Mast cells in pancreatic ductal adenocarcinoma. OncoImmunology 1:754–755, 2012.CrossRefGoogle Scholar
  13. 13.
    Chen, Y.-W., et al. SMAD4 Loss triggers the phenotypic changes of pancreatic ductal adenocarcinoma cells. BMC Cancer 14:181, 2014.CrossRefGoogle Scholar
  14. 14.
    Chin, L., Y. Xia, D. E. Discher, and P. A. Janmey. Mechanotransduction in cancer. Curr. Opin. Chem. Eng. 11:77–84, 2016.CrossRefGoogle Scholar
  15. 15.
    Cross, S. E., Y.-S. Jin, J. Rao, and J. K. Gimzewski. Nanomechanical analysis of cells from cancer patients. Nat. Nanotechnol. 2:780–783, 2007.CrossRefGoogle Scholar
  16. 16.
    Cuadrado, A., Z. Martin-Moldes, J. Ye, and I. Lastres-Becker. Transcription factors NRF2 and NF-κB are coordinated effectors of the rho family, GTP-binding protein RAC1 during inflammation. J. Biol. Chem. 289:15244–15258, 2014.CrossRefGoogle Scholar
  17. 17.
    Deer, E. L., et al. Phenotype and genotype of pancreatic cancer cell lines. Pancreas 39:425–435, 2010.CrossRefGoogle Scholar
  18. 18.
    Denais, C. M., et al. Nuclear envelope rupture and repair during cancer cell migration. Science 352:353–358, 2016.CrossRefGoogle Scholar
  19. 19.
    Dobin, A., et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29:15–21, 2013.CrossRefGoogle Scholar
  20. 20.
    Duxbury, M. S., S. W. Ashley, and E. E. Whang. Inhibition of pancreatic adenocarcinoma cellular invasiveness by blebbistatin: a novel myosin II inhibitor. Biochem. Biophys. Res. Commun. 313:992–997, 2004.CrossRefGoogle Scholar
  21. 21.
    Ellerbroek, S. M., Y. I. Wu, C. M. Overall, and M. S. Stack. Functional interplay between type I collagen and cell surface matrix metalloproteinase activity. J. Biol. Chem. 276:24833–24842, 2001.CrossRefGoogle Scholar
  22. 22.
    Ellerbroek, S. M., et al. Ovarian carcinoma regulation of matrix metalloproteinase-2 and membrane type 1 matrix metalloproteinase through beta1 integrin. Cancer Res. 59:1635–1641, 1999.Google Scholar
  23. 23.
    Engler, A. J., S. Sen, H. L. Sweeney, and D. E. Discher. Matrix elasticity directs stem cell lineage specification. Cell 126:677–689, 2006.CrossRefGoogle Scholar
  24. 24.
    Even-Ram, S., A. D. Doyle, M. A. Conti, K. Matsumoto, R. S. Adelstein, and K. M. Yamada. Myosin IIA regulates cell motility and actomyosin–microtubule crosstalk. Nat. Cell Biol. 9:299–309, 2007.CrossRefGoogle Scholar
  25. 25.
    Faria, E. C., et al. Measurement of elastic properties of prostate cancer cells using AFM. Analyst 133:1498, 2008.CrossRefGoogle Scholar
  26. 26.
    Fletcher, D. A., and R. D. Mullins. Cell mechanics and the cytoskeleton. Nature 463:485–492, 2010.CrossRefGoogle Scholar
  27. 27.
    Frantz, C., K. M. Stewart, and V. M. Weaver. The extracellular matrix at a glance. J. Cell Sci. 123:4195–4200, 2010.CrossRefGoogle Scholar
  28. 28.
    Fritzsche, M., C. Erlenkämper, E. Moeendarbary, G. Charras, and K. Kruse. Actin kinetics shapes cortical network structure and mechanics. Sci. Adv. 2:e1501337, 2016.CrossRefGoogle Scholar
  29. 29.
    Gardberg, M., et al. FHOD1, a formin upregulated in epithelial-mesenchymal transition, participates in cancer cell migration and invasion. PLoS ONE 8:e74923, 2013.CrossRefGoogle Scholar
  30. 30.
    Gardel, M. L., I. C. Schneider, Y. Aratyn-Schaus, and C. M. Waterman. Mechanical integration of actin and adhesion dynamics in cell migration. Annu. Rev. Cell Dev. Biol. 26:315–333, 2010.CrossRefGoogle Scholar
  31. 31.
    Goley, E. D., and M. D. Welch. The ARP2/3 complex: an actin nucleator comes of age. Nat. Rev. Mol. Cell Biol. 7:713–726, 2006.CrossRefGoogle Scholar
  32. 32.
    Harada, T., et al. Nuclear lamin stiffness is a barrier to 3D migration, but softness can limit survival. J. Cell Biol. 204:669–682, 2014.CrossRefGoogle Scholar
  33. 33.
    Harsha, H. C., et al. A compendium of potential biomarkers of pancreatic cancer. PLoS Med. 6:e1000046, 2009.CrossRefGoogle Scholar
  34. 34.
    Henson, J. H., et al. Arp2/3 complex inhibition radically alters lamellipodial actin architecture, suspended cell shape, and the cell spreading process. Mol. Biol. Cell 26:887–900, 2015.CrossRefGoogle Scholar
  35. 35.
    Hetrick, B., M. S. Han, L. A. Helgeson, and B. J. Nolen. Small molecules CK-666 and CK-869 inhibit actin-related protein 2/3 complex by blocking an activating conformational change. Chem. Biol. 20:701–712, 2013.CrossRefGoogle Scholar
  36. 36.
    Jaqaman, K., and S. Grinstein. Regulation from within: the cytoskeleton in transmembrane signaling. Trends Cell Biol. 22:515–526, 2012.CrossRefGoogle Scholar
  37. 37.
    Jimenez Valencia, A. M., et al. Collective cancer cell invasion induced by coordinated contractile stresses. Oncotarget 6:43438–43451, 2015.Google Scholar
  38. 38.
    Kalluri, R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nat. Rev. Cancer 3:422–433, 2003.CrossRefGoogle Scholar
  39. 39.
    Katt, M. E., A. L. Placone, A. D. Wong, Z. S. Xu, and P. C. Searson. In vitro tumor models: advantages, disadvantages, variables, and selecting the right platform. Front. Bioeng. Biotechnol. 4:12, 2016.CrossRefGoogle Scholar
  40. 40.
    Kim, S., and P. A. Coulombe. Emerging role for the cytoskeleton as an organizer and regulator of translation. Nat. Rev. Mol. Cell Biol. 11:75–81, 2010.CrossRefGoogle Scholar
  41. 41.
    Kim, H.-C., Y.-J. Jo, N.-H. Kim, and S. Namgoong. Small molecule inhibitor of formin homology 2 domains (SMIFH2) reveals the roles of the formin family of proteins in spindle assembly and asymmetric division in mouse oocytes. PLoS ONE 10:e0123438, 2015.CrossRefGoogle Scholar
  42. 42.
    Kim, T.-H., A. C. Rowat, and E. K. Sloan. Neural regulation of cancer: from mechanobiology to inflammation. Clin. Transl. Immunol. 5:e78, 2016.CrossRefGoogle Scholar
  43. 43.
    Kim, T.-H., et al. Cancer cells become less deformable and more invasive with activation of β-adrenergic signaling. J. Cell Sci. 129:4563–4575, 2016.CrossRefGoogle Scholar
  44. 44.
    Koenderink, G. H., et al. An active biopolymer network controlled by molecular motors. Proc. Natl. Acad. Sci. USA 106:15192–15197, 2009.CrossRefGoogle Scholar
  45. 45.
    Köhler, S., A. R. Bausch, M. Welch, J. Peloquin, and T. Svitkina. Contraction mechanisms in composite active actin networks. PLoS ONE 7:e39869, 2012.CrossRefGoogle Scholar
  46. 46.
    Kovács, M., J. Tóth, C. Hetényi, A. Málnási-Csizmadia, and J. R. Sellers. Mechanism of blebbistatin inhibition of myosin II. J. Biol. Chem. 279:35557–35563, 2004.CrossRefGoogle Scholar
  47. 47.
    Kraning-Rush, C. M., J. P. Califano, and C. A. Reinhart-King. Cellular traction stresses increase with increasing metastatic potential. PLoS ONE 7:e32572, 2012.CrossRefGoogle Scholar
  48. 48.
    Kumar, S., and V. M. Weaver. Mechanics, malignancy, and metastasis: the force journey of a tumor cell. Cancer Metastasis Rev. 28:113–127, 2009.CrossRefGoogle Scholar
  49. 49.
    Laevsky, G., and D. A. Knecht. Cross-linking of actin filaments by myosin II is a major contributor to cortical integrity and cell motility in restrictive environments. J. Cell Sci. 116:3761–3770, 2003.CrossRefGoogle Scholar
  50. 50.
    Liu, S., R. H. Goldstein, E. M. Scepansky, and M. Rosenblatt. Inhibition of rho-associated kinase signaling prevents breast cancer metastasis to human bone. Cancer Res. 69:8742–8751, 2009.CrossRefGoogle Scholar
  51. 51.
    Lopez, J. I., I. Kang, W.-K. You, D. M. McDonald, and V. M. Weaver. In situ force mapping of mammary gland transformation. Integr. Biol. 3:910, 2011.CrossRefGoogle Scholar
  52. 52.
    Maly, I. V., T. M. Domaradzki, V. A. Gosy, and W. A. Hofmann. Myosin isoform expressed in metastatic prostate cancer stimulates cell invasion. Sci. Rep. 7:8476, 2017.CrossRefGoogle Scholar
  53. 53.
    Matsubara, M., and M. J. Bissell. Inhibitors of Rho kinase (ROCK) signaling revert the malignant phenotype of breast cancer cells in 3D context. Oncotarget. 7:31602–31622, 2016.CrossRefGoogle Scholar
  54. 54.
    McBeath, R., D. M. Pirone, C. M. Nelson, K. Bhadriraju, and C. S. Chen. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev. Cell 6:483–495, 2004.CrossRefGoogle Scholar
  55. 55.
    Mendez, M. G., S.-I. Kojima, and R. D. Goldman. Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition. FASEB J. 24:1838–1851, 2010.CrossRefGoogle Scholar
  56. 56.
    Mey, I., A. Janshoff, J. Rother, and H. No. Atomic force microscopy-based microrheology reveals significant differences in the viscoelastic response between malign and benign cell lines. Open Biol. 4:140046, 2014.CrossRefGoogle Scholar
  57. 57.
    Mierke, C., D. Rosel, B. Fabry, and J. Brabek. Contractile forces in tumor cell migration. Eur. J. Cell Biol. 87:669–676, 2008.CrossRefGoogle Scholar
  58. 58.
    Mih, J. D., A. Marinkovic, F. Liu, A. S. Sharif, and D. J. Tschumperlin. Matrix stiffness reverses the effect of actomyosin tension on cell proliferation. J. Cell Sci. 125:5974–5983, 2012.CrossRefGoogle Scholar
  59. 59.
    Murrell, M., P. W. Oakes, M. Lenz, and M. L. Gardel. Forcing cells into shape: the mechanics of actomyosin contractility. Nat. Rev. Mol. Cell Biol. 16:486–498, 2015.CrossRefGoogle Scholar
  60. 60.
    Nakayama, M., et al. Rho-kinase and myosin II activities are required for cell type and environment specific migration. Genes Cells 10:107–117, 2005.CrossRefGoogle Scholar
  61. 61.
    Nguyen, A. V., et al. Stiffness of pancreatic cancer cells is associated with increased invasive potential. Integr. Biol. 8:1232–1245, 2016.CrossRefGoogle Scholar
  62. 62.
    Noël, A. C., et al. Invasion of reconstituted basement membrane matrix is not correlated to the malignant metastatic cell phenotype. Cancer Res. 51:405–414, 1991.Google Scholar
  63. 63.
    Nyberg, K. D., K. H. Hu, S. H. Kleinman, D. B. Khismatullin, M. J. Butte, and A. C. Rowat. Quantitative deformability cytometry (q-DC): rapid measurements of single cell viscoelastic properties. Biophys. J. 113:1574–1584, 2017.CrossRefGoogle Scholar
  64. 64.
    Nyberg, K. D., et al. Predicting cancer cell invasion by single-cell physical phenotyping. Integr. Biol. 10:218–231, 2018.CrossRefGoogle Scholar
  65. 65.
    Ouderkirk, J. L., and M. Krendel. Non-muscle myosins in tumor progression, cancer cell invasion, and metastasis. Cytoskeleton 71:447–463, 2014.CrossRefGoogle Scholar
  66. 66.
    Page-McCaw, A., A. J. Ewald, and Z. Werb. Matrix metalloproteinases and the regulation of tissue remodelling. Nat. Rev. Mol. Cell Biol. 8:221–233, 2007.CrossRefGoogle Scholar
  67. 67.
    Krakhmal, N. V., M. V. Zavyalova, E. V. Denisov, S. V. Vtorushin, and V. M. Perelmuter. Cancer invasion: patterns and mechanisms. Acta Nat. 7:17–28, 2015.CrossRefGoogle Scholar
  68. 68.
    Plodinec, M., et al. The nanomechanical signature of breast cancer. Nat. Nanotechnol. 7:757–765, 2012.CrossRefGoogle Scholar
  69. 69.
    Poincloux, R., et al. Contractility of the cell rear drives invasion of breast tumor cells in 3D Matrigel. Proc. Natl. Acad. Sci. USA 108:1943–1948, 2011.CrossRefGoogle Scholar
  70. 70.
    Provenzano, P. P., D. R. Inman, K. W. Eliceiri, S. M. Trier, and P. J. Keely. Contact guidance mediated three-dimensional cell migration is regulated by Rho/ROCK-dependent matrix reorganization. Biophys. J. 95:5374–5384, 2008.CrossRefGoogle Scholar
  71. 71.
    Pruyne, D., et al. Role of formins in actin assembly: nucleation and barbed-end association. Science 297:612–615, 2002.CrossRefGoogle Scholar
  72. 72.
    Raab, M., et al. ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death. Science 352:359–362, 2016.CrossRefGoogle Scholar
  73. 73.
    Rasheed, Z. A., W. Matsui, and A. Maitra. Pathology of pancreatic stroma in PDAC. In: Pancreatic Cancer and Tumor Microenvironment, edited by P. J. Grippo, and H. G. Munshi. Trivandrum: Transworld Research Network, 2012.Google Scholar
  74. 74.
    Rathje, L.-S. Z., et al. Oncogenes induce a vimentin filament collapse mediated by HDAC6 that is linked to cell stiffness. Proc. Natl. Acad. Sci. USA 111:1515–1520, 2014.CrossRefGoogle Scholar
  75. 75.
    Rauhala, H. E., S. Teppo, S. Niemelä, and A. Kallioniemi. Silencing of the ARP2/3 complex disturbs pancreatic cancer cell migration. Anticancer Res. 33:45–52, 2013.Google Scholar
  76. 76.
    Revach, O.-Y., A. Weiner, K. Rechav, I. Sabanay, A. Livne, and B. Geiger. Mechanical interplay between invadopodia and the nucleus in cultured cancer cells. Sci. Rep. 5:9466, 2015.CrossRefGoogle Scholar
  77. 77.
    Ridley, A. J. RhoA, RhoB and RhoC have different roles in cancer cell migration. J. Microsc. 251:242–249, 2013.CrossRefGoogle Scholar
  78. 78.
    Rizvi, S. A., et al. Identification and characterization of a small molecule inhibitor of formin-mediated actin assembly. Chem. Biol. 16:1158–1168, 2009.CrossRefGoogle Scholar
  79. 79.
    Rodriguez-Hernandez, I., G. Cantelli, F. Bruce, and V. Sanz-Moreno. Rho, ROCK and actomyosin contractility in metastasis as drug targets. F1000Research 5:783, 2016.CrossRefGoogle Scholar
  80. 80.
    Rowat, A. C., J. Lammerding, H. Herrmann, and U. Aebi. Towards an integrated understanding of the structure and mechanics of the cell nucleus. BioEssays 30:226–236, 2008.CrossRefGoogle Scholar
  81. 81.
    Rowat, A. C., et al. Nuclear envelope composition determines the ability of neutrophil-type cells to passage through micron-scale constrictions. J. Biol. Chem. 288:8610–8618, 2013.CrossRefGoogle Scholar
  82. 82.
    Salbreux, G., G. Charras, and E. Paluch. Actin cortex mechanics and cellular morphogenesis. Trends Cell Biol. 22:536–545, 2012.CrossRefGoogle Scholar
  83. 83.
    Sato, N., N. Maehara, G. H. Su, and M. Goggins. Effects of 5-Aza-2’-deoxycytidine on matrix metalloproteinase expression and pancreatic cancer cell invasiveness. J. Natl. Cancer Inst. 95:327–330, 2003.CrossRefGoogle Scholar
  84. 84.
    Sen, S., and S. Kumar. Cell-matrix de-adhesion dynamics reflect contractile mechanics. Cell. Mol. Bioeng. 2:218–230, 2009.CrossRefGoogle Scholar
  85. 85.
    Shi, Q., et al. A novel low-molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth. Mol. Carcinog. 46:488–496, 2007.CrossRefGoogle Scholar
  86. 86.
    Shields, M. A., S. Dangi-Garimella, S. B. Krantz, D. J. Bentrem, and H. G. Munshi. Pancreatic cancer cells respond to type I collagen by inducing snail expression to promote membrane type 1 matrix metalloproteinase-dependent collagen invasion. J. Biol. Chem. 286:10495–10504, 2011.CrossRefGoogle Scholar
  87. 87.
    Sipos, B., et al. Vascular endothelial growth factor mediated angiogenic potential of pancreatic ductal carcinomas enhanced by hypoxia: an in vitro and in vivo study. Int. J. Cancer 102:592–600, 2002.CrossRefGoogle Scholar
  88. 88.
    Smith, B. A., B. Tolloczko, J. G. Martin, and P. Grütter. Probing the viscoelastic behavior of cultured airway smooth muscle cells with atomic force microscopy: stiffening induced by contractile agonist. Biophys. J. 88:2994–3007, 2005.CrossRefGoogle Scholar
  89. 89.
    Sodek, K. L., T. J. Brown, and M. J. Ringuette. Collagen I but not Matrigel matrices provide an MMP-dependent barrier to ovarian cancer cell penetration. BMC Cancer 8:223, 2008.CrossRefGoogle Scholar
  90. 90.
    Southern, B. D., et al. Matrix-driven myosin II mediates the pro-fibrotic fibroblast phenotype. J. Biol. Chem. 291:6083–6095, 2016.CrossRefGoogle Scholar
  91. 91.
    Stossel, T. P., and J. H. Hartwig. Filling gaps in signaling to actin cytoskeletal remodeling. Dev. Cell 4:444–445, 2003.CrossRefGoogle Scholar
  92. 92.
    Strouch, M. J., et al. Crosstalk between mast cells and pancreatic cancer cells contributes to pancreatic tumor progression. Clin. Cancer Res. 16:2257–2265, 2010.CrossRefGoogle Scholar
  93. 93.
    Suraneni, P., B. Rubinstein, J. R. Unruh, M. Durnin, D. Hanein, and R. Li. The Arp2/3 complex is required for lamellipodia extension and directional fibroblast cell migration. J. Cell Biol. 197:239–251, 2012.CrossRefGoogle Scholar
  94. 94.
    Suraneni, P., et al. A mechanism of leading-edge protrusion in the absence of Arp2/3 complex. Mol. Biol. Cell 26:901–912, 2015.CrossRefGoogle Scholar
  95. 95.
    Swaminathan, V., K. Mythreye, E. Tim O’Brien, A. Berchuck, G. C. Blobe, and R. Superfine. Mechanical stiffness grades metastatic potential in patient tumor cells and in cancer cell lines. Cancer Res. 71:5075–5080, 2011.CrossRefGoogle Scholar
  96. 96.
    Swift, J., et al. Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. Science 341:1240104, 2013.CrossRefGoogle Scholar
  97. 97.
    Symowicz, J., et al. Engagement of collagen-binding integrins promotes matrix metalloproteinase-9-dependent E-cadherin ectodomain shedding in ovarian carcinoma cells. Cancer Res. 67:2030–2039, 2007.CrossRefGoogle Scholar
  98. 98.
    Takai, E., and S. Yachida. Genomic alterations in pancreatic cancer and their relevance to therapy. World J. Gastrointest. Oncol. 7:250–258, 2015.CrossRefGoogle Scholar
  99. 99.
    Tan, J. L., J. Tien, D. M. Pirone, D. S. Gray, K. Bhadriraju, and C. S. Chen. Cells lying on a bed of microneedles: An approach to isolate mechanical force. Proc. Natl. Acad. Sci. USA 100:1484–1489, 2003.CrossRefGoogle Scholar
  100. 100.
    Trapnell, C., et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat. Biotechnol. 28:511–515, 2010.CrossRefGoogle Scholar
  101. 101.
    Tse, H. T. K., et al. Quantitative diagnosis of malignant pleural effusions by single-cell mechanophenotyping. Sci. Transl. Med. 5:212ra163, 2013.CrossRefGoogle Scholar
  102. 102.
    Tseng, Y., et al. How actin crosslinking and bundling proteins cooperate to generate an enhanced cell mechanical response. Biochem. Biophys. Res. Commun. 334:183–192, 2005.CrossRefGoogle Scholar
  103. 103.
    Unbekandt, M., et al. A novel small-molecule MRCK inhibitor blocks cancer cell invasion. Cell Commun. Signal. 12:1–15, 2014.CrossRefGoogle Scholar
  104. 104.
    Vennin, C., et al. Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. Sci. Transl. Med. 9:eaai8504, 2017.CrossRefGoogle Scholar
  105. 105.
    Wang, Z.-M., D.-S. Yang, J. Liu, H.-B. Liu, M. Ye, and Y.-F. Zhang. ROCK inhibitor Y-27632 inhibits the growth, migration, and invasion of Tca8113 and CAL-27 cells in tongue squamous cell carcinoma. Tumor Biol. 37:3757–3764, 2016.CrossRefGoogle Scholar
  106. 106.
    Wei, L., M. Surma, S. Shi, N. Lambert-Cheatham, and J. Shi. Novel insights into the roles of rho kinase in cancer. Arch. Immunol. Ther. Exp. (Warsz) 64:259–278, 2016.CrossRefGoogle Scholar
  107. 107.
    Weng, S., Y. Shao, W. Chen, and J. Fu. Mechanosensitive subcellular rheostasis drives emergent single-cell mechanical homeostasis. Nat. Mater. 15:961–967, 2016.CrossRefGoogle Scholar
  108. 108.
    Wirtz, D., K. Konstantopoulos, and P. C. Searson. The physics of cancer: the role of physical interactions and mechanical forces in metastasis. Nat. Rev. Cancer 11:512–522, 2011.CrossRefGoogle Scholar
  109. 109.
    Wolf, K., et al. Physical limits of cell migration: control by ECM space and nuclear deformation and tuning by proteolysis and traction force. J. Cell Biol. 201:1069–1084, 2013.CrossRefGoogle Scholar
  110. 110.
    Xiao, F., X. Wen, and P. Y. Chiou. Plasmonic micropillars for massively parallel precision cell force measurement. Micro Electro Mech. Syst. 1:243–246, 2017.Google Scholar
  111. 111.
    Xiao, F., X. Wen, X. H. M. Tan, and P.-Y. Chiou. Plasmonic micropillars for precision cell force measurement across a large field-of-view. Appl. Phys. Lett. 112:033701, 2018.CrossRefGoogle Scholar
  112. 112.
    Xu, W., R. Mezencev, B. Kim, L. Wang, J. McDonald, and T. Sulchek. Cell stiffness is a biomarker of the metastatic potential of ovarian cancer cells. PLoS ONE 7:e46609, 2012.CrossRefGoogle Scholar
  113. 113.
    Yachida, S., et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467:1114–1117, 2010.CrossRefGoogle Scholar
  114. 114.
    Yamaguchi, H., and J. Condeelis. Regulation of the actin cytoskeleton in cancer cell migration and invasion. Biochim. Biophys. Acta 1773:642–652, 2007.CrossRefGoogle Scholar
  115. 115.
    Ying, H., et al. The Rho kinase inhibitor fasudil inhibits tumor progression in human and rat tumor models. Mol. Cancer Ther. 5:2158–2164, 2006.CrossRefGoogle Scholar
  116. 116.
    Yu, H. W., et al. PIX controls intracellular viscoelasticity to regulate lung cancer cell migration. J. Cell Mol. Med. 19:934–947, 2015.CrossRefGoogle Scholar
  117. 117.
    Zaidel-Bar, R., G. Zhenhuan, and C. Luxenburg. The contractome—a systems view of actomyosin contractility in non-muscle cells. J. Cell Sci. 128:1–9, 2015.CrossRefGoogle Scholar
  118. 118.
    Zhang, W., et al. Microfluidics separation reveals the stem-cell-like deformability of tumor-initiating cells. Proc. Natl. Acad. Sci. USA 109:18707–18712, 2012.CrossRefGoogle Scholar
  119. 119.
    Zhao, S., Y. Wang, L. Cao, M. M. Ouellette, and J. W. Freeman. Expression of oncogenic K-ras and loss of Smad4 cooperate to induce the expression of EGFR and to promote invasion of immortalized human pancreas ductal cells. Int. J. Cancer 127:2076–2087, 2010.CrossRefGoogle Scholar
  120. 120.
    Zhao, X., et al. Hypoxia-Inducible factor-1 promotes pancreatic ductal adenocarcinoma invasion and metastasis by activating transcription of the actin-Bundling protein fascin. Cancer Res. 74:2455–2464, 2014.CrossRefGoogle Scholar
  121. 121.
    Zhou, L., et al. Theoretical modeling of mechanical homeostasis of a mammalian cell under gravity-directed vector. Biomech. Model. Mechanobiol. 17:191–203, 2018.CrossRefGoogle Scholar
  122. 122.
    Zhu, F., et al. Rho kinase inhibitor fasudil suppresses migration and invasion though down-regulating the expression of VEGF in lung cancer cell line A549. Med. Oncol. 28:565–571, 2011.CrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society 2019

Authors and Affiliations

  • Angelyn V. Nguyen
    • 1
  • Brittany Trompetto
    • 1
  • Xing Haw Marvin Tan
    • 2
  • Michael B. Scott
    • 1
    • 7
    • 9
    • 10
  • Kenneth Hsueh-heng Hu
    • 3
  • Eric Deeds
    • 1
    • 4
  • Manish J. Butte
    • 5
    • 6
  • Pei Yu Chiou
    • 2
    • 7
  • Amy C. Rowat
    • 1
    • 2
    • 8
    Email author
  1. 1.Department of Integrative Biology and PhysiologyUniversity of CaliforniaLos AngelesUSA
  2. 2.Department of BioengineeringUniversity of CaliforniaLos AngelesUSA
  3. 3.Stanford BiophysicsStanford UniversityStanfordUSA
  4. 4.Institute for Quantitative and Computational BiologyUniversity of CaliforniaLos AngelesUSA
  5. 5.Department of PediatricsUniversity of CaliforniaLos AngelesUSA
  6. 6.Department of Microbiology, Immunology, and Molecular GeneticsUniversity of CaliforniaLos AngelesUSA
  7. 7.Department of Mechanical and Aerospace EngineeringUniversity of CaliforniaLos AngelesUSA
  8. 8.Jonsson Comprehensive Cancer CenterUniversity of CaliforniaLos AngelesUSA
  9. 9.Department of RadiologyNorthwestern University Feinberg School of MedicineChicagoUSA
  10. 10.Department of Biomedical EngineeringNorthwestern McCormick School of EngineeringEvanstonUSA

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