Rho-ROCK Signaling in Normal Physiology and as a Key Player in Shaping the Tumor Microenvironment

  • Sean Porazinski
  • Ashleigh Parkin
  • Marina PajicEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1223)


The Rho-ROCK signaling network has a range of specialized functions of key biological importance, including control of essential developmental processes such as morphogenesis and physiological processes including homeostasis, immunity, and wound healing. Deregulation of Rho-ROCK signaling actively contributes to multiple pathological conditions, and plays a major role in cancer development and progression. This dynamic network is critical in modulating the intricate communication between tumor cells, surrounding diverse stromal cells and the matrix, shaping the ever-changing microenvironment of aggressive tumors. In this chapter, we overview the complex regulation of the Rho-ROCK signaling axis, its role in health and disease, and analyze progress made with key approaches targeting the Rho-ROCK pathway for therapeutic benefit. Finally, we conclude by outlining likely future trends and key questions in the field of Rho-ROCK research, in particular surrounding Rho-ROCK signaling within the tumor microenvironment.


Rho-ROCK signaling Tumor microenvironment Stroma Pancreatic cancer Disease Development Actomyosin cytoskeleton Metastasis Extracellular matrix Targeted therapy ROCK inhibitors 



Marina Pajic acknowledges fellowship support from the NHMRC 1162556, Cancer Institute NSW and Philip Hemstritch philanthropic fellowship, with project grant support from the NHMRC 1162860 and Cancer Australia, Cancer Council NSW 1143699.


  1. 1.
    Amin E et al (2013) Rho-kinase: regulation, (dys)function, and inhibition. Biol Chem 394(11):1399–1410PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Chin VT et al (2015) Rho-associated kinase signalling and the cancer microenvironment: novel biological implications and therapeutic opportunities. Expert Rev Mol Med 17:e17PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Koch JC, Tatenhorst L, Roser A-E, Saal K-A, Tönges L, Lingor P (Sep. 2018) ROCK inhibition in models of neurodegeneration and its potential for clinical translation. Pharmacol Ther 189:1–21PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Cai A, Li L, Zhou Y (2016) Pathophysiological effects of RhoA and Rho-associated kinase on cardiovascular system. J Hypertens 34(1):3–10PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Knipe RS et al (2017) The rho kinase isoforms ROCK1 and ROCK2 each contribute to the development of experimental pulmonary fibrosis. Am J Respir Cell Mol Biol 58(4):471–481CrossRefGoogle Scholar
  6. 6.
    Okimoto S et al (2019) Vitamin A-coupled liposomal rho-kinase inhibitor ameliorates liver fibrosis without systemic adverse effects. Hepatol Res 49(6):663–675PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Lenti MV, Di Sabatino A (2019) Intestinal fibrosis. Mol Asp Med 65:100–109CrossRefGoogle Scholar
  8. 8.
    Thompson JM et al (2017) Rho-associated kinase 1 inhibition is synthetically lethal with von Hippel-Lindau deficiency in clear cell renal cell carcinoma. Oncogene 36(8):1080–1089PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Kamai T et al (2003) Significant association of rho/ROCK pathway with invasion and metastasis of bladder cancer. Clin Cancer Res 9:2632–2641PubMedPubMedCentralGoogle Scholar
  10. 10.
    Liu S (2011) The ROCK signaling and breast cancer metastasis. Mol Biol Rep 38(2):1363–1366PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Rath N et al (2018) Rho kinase inhibition by AT13148 blocks pancreatic ductal adenocarinoma invasion and tumor growth. Cancer Res 78(12):3321–3336Google Scholar
  12. 12.
    Defert O, Boland S (2017) Rho kinase inhibitors: a patent review (2014–2016). Expert Opin Ther Pat 27(4):507–515PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Nakagawa O, Fujisawa K, Ishizaki T, Saito Y, Nakao K, Narumiya S (1996) ROCK-I and ROCK-II, two isoforms of rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett 392(2):189–193PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Morgan-Fisher M, Wewer UM, Yoneda A (2013) Regulation of ROCK activity in cancer. J Histochem Cytochem 61(3):185–198PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Kher SS, Worthylake RA (2011) Regulation of ROCKII membrane localization through its C-terminus. Exp Cell Res 317(20):2845–2852PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Ishiuchi T, Takeichi M (2011) Willin and Par3 cooperatively regulate epithelial apical constriction through aPKC-mediated ROCK phosphorylation. Nat Cell Biol 13(7):860–866PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    McCormack J, Welsh NJ, Braga VMM (2013) Cycling around cell-cell adhesion with Rho GTPase regulators. J Cell Sci 126(2):379–391PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Timpson P, Jones GE, Frame MC, Brunton VG (2001) Coordination of cell polarization and migration by the rho family GTPases requires Src tyrosine kinase activity. Curr Biol 11(23):1836–1846PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Lebowitz PF, Davide JP, Prendergast GC (1995) Evidence that farnesyltransferase inhibitors suppress Ras transformation by interfering with Rho activity. Mol Cell Biol 15(12):6613–6622PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Wennerberg K, Der CJ (2004) Rho-family GTPases: it’s not only Rac and Rho (and I like it). J Cell Sci 117(8):1301–1312PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Cherfils J, Zeghouf M (2013) Regulation of small GTPases by GEFs, GAPs, and GDIs. Physiol Rev 93(1):269–309PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Fritz RD, Pertz O (2016) The dynamics of spatio-temporal rho GTPase signaling: formation of signaling patterns. F1000Res 5Google Scholar
  23. 23.
    Ishizaki T et al (1996) The small GTP-binding protein rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase. EMBO J 15(8):1885–1893PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Conway A-M, James AB, O’Kane EM, Rakhit S, Morris BJ (2004) Regulation of myosin light chain phosphorylation by RhoB in neuronal cells. Exp Cell Res 300(1):35–42PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Watanabe N et al (1997) p140mDia, a mammalian homolog of Drosophila diaphanous, is a target protein for Rho small GTPase and is a ligand for profilin. EMBO J 16(11):3044–3056PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Ward Y et al (2002) The GTP binding proteins Gem and Rad are negative regulators of the Rho-Rho kinase pathway. J Cell Biol 157(2):291–302PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Riento K, Guasch RM, Garg R, Jin B, Ridley AJ (2003) RhoE binds to ROCK I and inhibits downstream signaling. Mol Cell Biol 23(12):4219–4229PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Araki S et al (2001) Arachidonic acid-induced Ca2+ sensitization of smooth muscle contraction through activation of Rho-kinase. Pflugers Arch 441(5):596–603PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Yoneda A, Multhaupt HAB, Couchman JR (2005) The Rho kinases I and II regulate different aspects of myosin II activity. J Cell Biol 170(3):443–453PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Strzelecka-Kiliszek A, Mebarek S, Roszkowska M, Buchet R, Magne D, Pikula S (2017) Functions of Rho family of small GTPases and Rho-associated coiled-coil kinases in bone cells during differentiation and mineralization. Biochim Biophys Acta Gen Subj 1861(5 Pt A):1009–1023PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Jaffe AB, Hall A (2005) RHO GTPASES: biochemistry and biology. Annu Rev Cell Dev Biol 21(1):247–269PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Pajic M et al (2015) The dynamics of rho GTPase signaling and implications for targeting cancer and the tumor microenvironment. Small GTPases 6(2):123–133PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Wang Y et al (2009) ROCK isoform regulation of myosin phosphatase and contractility in vascular smooth muscle cells. Circ Res 104(4):531–540PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Schofield AV, Bernard O (2013) Rho-associated coiled-coil kinase (ROCK) signaling and disease. Crit Rev Biochem Mol Biol 48(4):301–316PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Asp P, Wihlborg M, Karlén M, Farrants A-KO (2002) Expression of BRG1, a human SWI/SNF component, affects the organisation of actin filaments through the RhoA signalling pathway. J Cell Sci 115(Pt 13):2735–2746PubMedPubMedCentralGoogle Scholar
  36. 36.
    Rath N, Olson MF (2012) Rho-associated kinases in tumorigenesis: re-considering ROCK inhibition for cancer therapy. EMBO Rep 13(10):900–908PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Kadir S, Astin JW, Tahtamouni L, Martin P, Nobes CD (2011) Microtubule remodelling is required for the front-rear polarity switch during contact inhibition of locomotion. J Cell Sci 124(Pt 15):2642–2653PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Lowery DM et al (2007) Proteomic screen defines the Polo-box domain interactome and identifies Rock2 as a Plk1 substrate. EMBO J 26(9):2262–2273PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Kanai M, Crowe MS, Zheng Y, Vande Woude GF, Fukasawa K (2010) RhoA and RhoC are both required for the ROCK II-dependent promotion of centrosome duplication. Oncogene 29(45):6040–6050PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Hanashiro K, Brancaccio M, Fukasawa K (2011) Activated ROCK II by-passes the requirement of the CDK2 activity for centrosome duplication and amplification. Oncogene 30(19):2188–2197PubMedCrossRefGoogle Scholar
  41. 41.
    Croft DR, Olson MF (2006) The rho GTPase effector ROCK regulates cyclin A, cyclin D1, and p27Kip1 levels by distinct mechanisms. Mol Cell Biol 26(12):4612–4627PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Samuel MS et al (2011) Actomyosin-mediated cellular tension drives increased tissue stiffness and β-catenin activation to induce epidermal hyperplasia and tumor growth. Cancer Cell 19(6):776–791PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Street CA, Bryan BA (2011) Rho kinase proteins—pleiotropic modulators of cell survival and apoptosis. Anticancer Res 31(11):3645–3657PubMedPubMedCentralGoogle Scholar
  44. 44.
    Lock FE, Hotchin NA (2009) Distinct roles for ROCK1 and ROCK2 in the regulation of keratinocyte differentiation. PLoS One 4(12):e8190PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Palanivel R, Ganguly R, Turdi S, Xu A, Sweeney G (2014) Adiponectin stimulates rho-mediated actin cytoskeleton remodeling and glucose uptake via APPL1 in primary cardiomyocytes. Metabolism 63(10):1363–1373PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Laufs U et al (2000) Neuroprotection mediated by changes in the endothelial actin cytoskeleton. J Clin Invest 106(1):15–24PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Wang L, Yang L, Luo Y, Zheng Y (2003) A novel strategy for specifically down-regulating individual Rho GTPase activity in tumor cells. J Biol Chem 278(45):44617–44625PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Ridley AJ (2013) RhoA, RhoB and RhoC have different roles in cancer cell migration. J Microsc 251(3):242–249CrossRefGoogle Scholar
  49. 49.
    Sin WC, Chen XQ, Leung T, Lim L (1998) RhoA-binding kinase alpha translocation is facilitated by the collapse of the vimentin intermediate filament network. Mol Cell Biol 18(11):6325–6339PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Chen X, Tan I, Ng CH, Hall C, Lim L, Leung T (2002) Characterization of RhoA-binding kinase ROKalpha implication of the pleckstrin homology domain in ROKalpha function using region-specific antibodies. J Biol Chem 277(15):12680–12688PubMedCrossRefGoogle Scholar
  51. 51.
    Kimura K et al (1998) Regulation of the association of adducin with actin filaments by Rho-associated kinase (Rho-kinase) and myosin phosphatase. J Biol Chem 273(10):5542–5548PubMedCrossRefGoogle Scholar
  52. 52.
    Momotani K, Somlyo AV (2012) p63RhoGEF: a new switch for G(q)-mediated activation of smooth muscle. Trends Cardiovasc Med 22(5):122–127PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Zou W, Teitelbaum SL (2010) Integrins, growth factors, and the osteoclast cytoskeleton. Ann N Y Acad Sci 1192:27–31PubMedCrossRefGoogle Scholar
  54. 54.
    Tybulewicz VLJ, Henderson RB (2009) Rho family GTPases and their regulators in lymphocytes. Nat Rev Immunol 9(9):630–644PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Iden S, Collard JG (2008) Crosstalk between small GTPases and polarity proteins in cell polarization. Nat Rev Mol Cell Biol 9(11):846–859PubMedCrossRefGoogle Scholar
  56. 56.
    Dvorsky R, Ahmadian MR (2004) Always look on the bright site of Rho: structural implications for a conserved intermolecular interface. EMBO Rep 5(12):1130–1136PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Herbrand U, Ahmadian MR (2006) p190-RhoGAP as an integral component of the Tiam1/Rac1-induced downregulation of Rho. Biol Chem 387(3):311–317PubMedCrossRefGoogle Scholar
  58. 58.
    Zieba BJ et al (2011) The cAMP-responsive Rap1 guanine nucleotide exchange factor, Epac, induces smooth muscle relaxation by down-regulation of RhoA activity. J Biol Chem 286(19):16681–16692PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Larrea MD et al (2009) RSK1 drives p27Kip1 phosphorylation at T198 to promote RhoA inhibition and increase cell motility. Proc Natl Acad Sci U S A 106(23):9268–9273PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Valderrama F, Cordeiro JV, Schleich S, Frischknecht F, Way M (2006) Vaccinia virus-induced cell motility requires F11L-mediated inhibition of RhoA signaling. Science 311(5759):377–381PubMedCrossRefGoogle Scholar
  61. 61.
    Duan X, Chen K-L, Zhang Y, Cui X-S, Kim N-H, Sun S-C (2014) ROCK inhibition prevents early mouse embryo development. Histochem Cell Biol 142(2):227–233PubMedCrossRefGoogle Scholar
  62. 62.
    Marikawa Y, Alarcon VB (2012) Creation of trophectoderm, the first epithelium, in mouse preimplantation development. Results Probl Cell Differ 55:165–184PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Hirate Y et al (2013) Polarity-dependent distribution of angiomotin localizes Hippo signaling in preimplantation embryos. Curr Biol 23(13):1181–1194PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Alarcon VB, Marikawa Y (2018) ROCK and RHO playlist for Preimplantation development: streaming to HIPPO pathway and Apicobasal polarity in the first cell differentiation. Adv Anat Embryol Cell Biol 229:47–68PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Marikawa Y, Alarcon VB (2019) RHOA activity in expanding blastocysts is essential to regulate HIPPO-YAP signaling and to maintain the trophectoderm-specific gene expression program in a ROCK/actin filament-independent manner. MHR Basic Sci Reprod Med 25(2):43–60CrossRefGoogle Scholar
  66. 66.
    Motomura K et al (2017) A rho-associated coiled-coil containing kinases (ROCK) inhibitor, Y-27632, enhances adhesion, viability and differentiation of human term placenta-derived trophoblasts in vitro. PLoS One 12(5):e0177994PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Watanabe K et al (2007) A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nat Biotechnol 25(6):681–686PubMedCrossRefGoogle Scholar
  68. 68.
    Ohgushi M et al (2010) Molecular pathway and cell state responsible for dissociation-induced apoptosis in human pluripotent stem cells. Cell Stem Cell 7(2):225–239PubMedCrossRefGoogle Scholar
  69. 69.
    Samuel MS, Olson MF (2011) Rho-GTPases in embryonic stem cells. Embryonic Stem Cells Basic Biol BioengGoogle Scholar
  70. 70.
    Kiecker C, Bates T, Bell E (2016) Molecular specification of germ layers in vertebrate embryos. Cell Mol Life Sci 73(5):923–947PubMedCrossRefGoogle Scholar
  71. 71.
    Kim K, Ossipova O, Sokol SY (2015) Neural crest specification by inhibition of the ROCK/Myosin II pathway. Stem Cells 33(3):674–685PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Srinivasan A, Chang S-Y, Zhang S, Toh WS, Toh Y-C (2018) Substrate stiffness modulates the multipotency of human neural crest derived ectomesenchymal stem cells via CD44 mediated PDGFR signaling. Biomaterials 167:153–167PubMedCrossRefGoogle Scholar
  73. 73.
    Laeno AMA, Tamashiro DAA, Alarcon VB (2013) Rho-associated kinase activity is required for proper morphogenesis of the inner cell mass in the mouse blastocyst. Biol Reprod 89(5):122PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Li L, Arman E, Ekblom P, Edgar D, Murray P, Lonai P (2004) Distinct GATA6- and laminin-dependent mechanisms regulate endodermal and ectodermal embryonic stem cell fates. Development 131(21):5277–5286PubMedCrossRefGoogle Scholar
  75. 75.
    Loebel DAF, Tam PPL (2012) Rho GTPases in endoderm development and differentiation. Small GTPases 3(1):40–44PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Maldonado M, Luu RJ, Ramos MEP, Nam J (2016) ROCK inhibitor primes human induced pluripotent stem cells to selectively differentiate towards mesendodermal lineage via epithelial-mesenchymal transition-like modulation. Stem Cell Res 17(2):222–227PubMedCrossRefGoogle Scholar
  77. 77.
    Joo HJ et al (2012) ROCK suppression promotes differentiation and expansion of endothelial cells from embryonic stem cell-derived Flk1(+) mesodermal precursor cells. Blood 120(13):2733–2744PubMedCrossRefGoogle Scholar
  78. 78.
    Lawson CD, Ridley AJ (2018) Rho GTPase signaling complexes in cell migration and invasion. J Cell Biol 217(2):447–457PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    LaMonica K, Grabel L (2012) The planar cell polarity pathway and parietal endoderm cell migration. In: Turksen K (ed) Planar cell polarity: methods and protocols. Springer, New York, pp 187–200CrossRefGoogle Scholar
  80. 80.
    Stankova V, Tsikolia N, Viebahn C (2015) Rho kinase activity controls directional cell movements during primitive streak formation in the rabbit embryo. Development 142(1):92–98PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Berndt JD, Clay MR, Langenberg T, Halloran MC (2008) Rho-kinase and myosin II affect dynamic neural crest cell behaviors during epithelial to mesenchymal transition in vivo. Dev Biol 324(2):236–244PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Kuriyama S, Mayor R (2008) Molecular analysis of neural crest migration. Philos Trans R Soc Lond B Biol Sci 363(1495):1349–1362PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Wei L et al (2001) Rho kinases play an obligatory role in vertebrate embryonic organogenesis. Development 128(15):2953–2962PubMedPubMedCentralGoogle Scholar
  84. 84.
    Rolo A, Escuin S, Greene NDE, Copp AJ (2018) Rho GTPases in mammalian spinal neural tube closure. Small GTPases 9(4):283–289PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Borges RM, Lamers ML, Forti FL, Santos MFD, Yan CYI (2011) Rho signaling pathway and apical constriction in the early lens placode. Genes N Y N 2000 49(5):368–379Google Scholar
  86. 86.
    Chauhan BK et al (2009) Cdc42- and IRSp53-dependent contractile filopodia tether presumptive lens and retina to coordinate epithelial invagination. Development 136(21):3657–3667PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Chauhan BK, Lou M, Zheng Y, Lang RA (2011) Balanced Rac1 and RhoA activities regulate cell shape and drive invagination morphogenesis in epithelia. Proc Natl Acad Sci U S A 108(45):18289–18294PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Porazinski S et al (2015) YAP is essential for tissue tension to ensure vertebrate 3D body shape. Nature 521(7551):217–221PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Dupont S et al (2011) Role of YAP/TAZ in mechanotransduction. Nature 474(7350):179–183PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Boyle ST, Kular J, Nobis M, Ruszkiewicz A, Timpson P, Samuel MS (2018) Acute compressive stress activates RHO/ROCK-mediated cellular processes. Small GTPases 1–17Google Scholar
  91. 91.
    Eiraku M et al (2011) Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 472(7341):51–56CrossRefGoogle Scholar
  92. 92.
    Chen G, Hou Z, Gulbranson DR, Thomson JA (2010) Actin-myosin contractility is responsible for the reduced viability of dissociated human embryonic stem cells. Cell Stem Cell 7(2):240–248PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Romani P et al (2019) Extracellular matrix mechanical cues regulate lipid metabolism through Lipin-1 and SREBP. Nat Cell Biol 21(3):338–347PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Narumiya S, Thumkeo D (2018) Rho signaling research: history, current status and future directions. FEBS Lett 592(11):1763–1776PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Takano T et al (2017) Discovery of long-range inhibitory signaling to ensure single axon formation. Nat Commun 8(1):33PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Shinohara R et al (2012) A role for mDia, a rho-regulated actin nucleator, in tangential migration of interneuron precursors. Nat Neurosci 15(3):373–380PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Tashiro A, Minden A, Yuste R (2000) Regulation of dendritic spine morphology by the rho family of small GTPases: antagonistic roles of Rac and rho. Cereb Cortex 10(10):927–938PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Czeisler C et al (2016) Surface topography during neural stem cell differentiation regulates cell migration and cell morphology. J Comp Neurol 524(17):3485–3502PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Julian L, Olson MF (2014) Rho-associated coiled-coil containing kinases (ROCK). Small GTPases 5(2):e29846PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Vicente-Steijn R et al (2017) RHOA-ROCK signalling is necessary for lateralization and differentiation of the developing sinoatrial node. Cardiovasc Res 113(10):1186–1197PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Moore KA et al (2005) Control of basement membrane remodeling and epithelial branching morphogenesis in embryonic lung by rho and cytoskeletal tension. Dev Dyn 232(2):268–281PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Toyoda T et al (2017) Rho-associated kinases and non-muscle Myosin IIs inhibit the differentiation of human iPSCs to pancreatic endoderm. Stem Cell Rep 9(2):419–428CrossRefGoogle Scholar
  103. 103.
    Korostylev A et al (2017) A high-content small molecule screen identifies novel inducers of definitive endoderm. Mol Metab 6(7):640–650PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Ghazizadeh Z et al (2017) ROCKII inhibition promotes the maturation of human pancreatic beta-like cells. Nat Commun 8(1):298PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Kular J et al (2015) A negative regulatory mechanism involving 14-3-3ζ limits Signaling downstream of ROCK to regulate tissue stiffness in epidermal homeostasis. Dev Cell 35(6):759–774PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Butcher DT, Alliston T, Weaver VM (2009) A tense situation: forcing tumour progression. Nat Rev Cancer 9(2):108–122PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Hay ED (1995) An overview of epithelio-mesenchymal transformation. Acta Anat (Basel) 154(1):8–20CrossRefGoogle Scholar
  108. 108.
    Markowski MC, Brown AC, Barker TH (2012) Directing epithelial to mesenchymal transition through engineered microenvironments displaying orthogonal adhesive and mechanical cues. J Biomed Mater Res A 100(8):2119–2127PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Yang J-Q et al (2016) RhoA orchestrates glycolysis for TH2 cell differentiation and allergic airway inflammation. J Allergy Clin Immunol 137(1):231–245.e4PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Song J et al (2019) Inhibition of ROCK activity regulates the balance of Th1, Th17 and Treg cells in myasthenia gravis. Clin Immunol 203:142–153PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Zanin-Zhorov A et al (2014) Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proc Natl Acad Sci U S A 111(47):16814–16819PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Zanin-Zhorov A et al (2017) Cutting edge: selective Oral ROCK2 inhibitor reduces clinical scores in patients with psoriasis vulgaris and normalizes skin pathology via concurrent regulation of IL-17 and IL-10. J Immunol 198(10):3809–3814PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Zanin-Zhorov A, Waksal SD (2015) ROCKing cytokine secretion balance in human T cells. Cytokine 72(2):224–225PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Kanzaki M, Pessin JE (2001) Insulin-stimulated GLUT4 translocation in adipocytes is dependent upon cortical actin remodeling. J Biol Chem 276(45):42436–42444PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Török D et al (2004) Insulin but not PDGF relies on actin remodeling and on VAMP2 for GLUT4 translocation in myoblasts. J Cell Sci 117(Pt 22):5447–5455PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Furukawa N et al (2005) Role of Rho-kinase in regulation of insulin action and glucose homeostasis. Cell Metab 2(2):119–129PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Lee DH et al (2009) Targeted disruption of ROCK1 causes insulin resistance in vivo. J Biol Chem 284(18):11776–11780PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Chun K-H et al (2012) Regulation of glucose transport by ROCK1 differs from that of ROCK2 and is controlled by Actin polymerization. Endocrinology 153(4):1649–1662PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Stirling L, Williams MR, Morielli AD (2009) Dual roles for RHOA/RHO-kinase in the regulated trafficking of a voltage-sensitive potassium channel. Mol Biol Cell 20(12):2991–3002PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Li H et al (2016) Y-27632, a Rho-associated protein kinase inhibitor, inhibits voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells. Pharmacology 98(5–6):220–227PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Rousset M et al (2015) Regulation of neuronal high-voltage activated Ca(V)2 Ca(2+) channels by the small GTPase RhoA. Neuropharmacology 97:201–209PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Ureña J, López-Barneo J (2012) Metabotropic regulation of RhoA/rho-associated kinase by L-type Ca2+ channels. Trends Cardiovasc Med 22(6):155–160PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Henderson BW et al (2016) Rho-associated protein kinase 1 (ROCK1) is increased in Alzheimer’s disease and ROCK1 depletion reduces amyloid-β levels in brain. J Neurochem 138(4):525–531PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Fujimura M, Usuki F, Nakamura A (2019) Fasudil, a rho-associated coiled coil-forming protein kinase inhibitor, recovers Methylmercury-induced axonal degeneration by changing microglial phenotype in rats. Toxicol Sci 168(1):126–136PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Shimizu T, Liao JK (2016) Rho kinases and cardiac Remodeling. Circ J 80(7):1491–1498PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Bailey KE et al (2019) Disruption of embryonic ROCK signaling reproduces the sarcomeric phenotype of hypertrophic cardiomyopathy. JCI Insight 5Google Scholar
  127. 127.
    Komers R (2013) Rho kinase inhibition in diabetic kidney disease. Br J Clin Pharmacol 76(4):551–559PubMedPubMedCentralGoogle Scholar
  128. 128.
    Stanley A, Heo S, Mauck RL, Mourkioti F, Shore EM (2019) Elevated BMP and mechanical signaling through YAP1/RhoA poises FOP Mesenchymal progenitors for Osteogenesis. J Bone Miner Res 34:1894–1909PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Wang Y-X et al (2005) Inhibition of Rho-kinase by fasudil attenuated angiotensin II-induced cardiac hypertrophy in apolipoprotein E deficient mice. Eur J Pharmacol 512(2–3):215–222PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Prior IA, Lewis PD, Mattos C (2012) A comprehensive survey of Ras mutations in cancer. Cancer Res 72(10):2457–2467PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Kandoth C et al (2013) Mutational landscape and significance across 12 major cancer types. Nature 502(7471):333–339PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Waddell N et al (2015) Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518(7540):495–501PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Olson MF (2018) Rho GTPases, their post-translational modifications, disease-associated mutations and pharmacological inhibitors. Small GTPases 9(3):203–215PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Hodis E et al (2012) A landscape of driver mutations in melanoma. Cell 150(2):251–263PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Krauthammer M et al (2012) Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet 44(9):1006–1014PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Kawazu M et al (2013) Transforming mutations of RAC guanosine triphosphatases in human cancers. Proc Natl Acad Sci U S A 110(8):3029–3034PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Yoo HY et al (2014) A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma. Nat Genet 46(4):371–375PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Sakata-Yanagimoto M et al (2014) Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet 46(2):171–175PubMedCrossRefPubMedCentralGoogle Scholar
  139. 139.
    Kakiuchi M et al (2014) Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. Nat Genet 46(6):583–587PubMedCrossRefPubMedCentralGoogle Scholar
  140. 140.
    Dyberg C et al (2017) Rho-associated kinase is a therapeutic target in neuroblastoma. Proc Natl Acad Sci U S A 114(32):E6603–E6612PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Wei L, Surma M, Shi S, Lambert-Cheatham N, Shi J (2016) Novel insights into the roles of Rho kinase in cancer. Arch Immunol Ther Exp 64(4):259–278CrossRefGoogle Scholar
  142. 142.
    Itoh K, Yoshioka K, Akedo H, Uehata M, Ishizaki T, Narumiya S (1999) An essential part for Rho-associated kinase in the transcellular invasion of tumor cells. Nat Med 5(2):221–225PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Olson MF, Sahai E (2008) The actin cytoskeleton in cancer cell motility. Clin Exp Metastasis 26(4):273PubMedCrossRefPubMedCentralGoogle Scholar
  144. 144.
    Sadok A, Marshall CJ (2014) Rho GTPases: masters of cell migration. Small GTPases 5:e29710PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Vega FM, Fruhwirth G, Ng T, Ridley AJ (2011) RhoA and RhoC have distinct roles in migration and invasion by acting through different targets. J Cell Biol 193(4):655–665PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Vega FM, Colomba A, Reymond N, Thomas M, Ridley AJ (2012) RhoB regulates cell migration through altered focal adhesion dynamics. Open Biol 2(5):120076PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Gong X, Didan Y, Lock JG, Strömblad S (2018) KIF13A-regulated RhoB plasma membrane localization governs membrane blebbing and blebby amoeboid cell migration. EMBO J 37(17)Google Scholar
  148. 148.
    Suwa H et al (1998) Overexpression of the rhoC gene correlates with progression of ductal adenocarcinoma of the pancreas. Br J Cancer 77(1):147–152PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Binnewies M et al (2018) Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med 24(5):541PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    LeBleu VS, Kalluri R (2018) A peek into cancer-associated fibroblasts: origins, functions and translational impact. Dis Model Mech 11(4):dmm029447PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Boyle ST, Samuel MS (2016) Mechano-reciprocity is maintained between physiological boundaries by tuning signal flux through the rho-associated protein kinase. Small GTPases 7(3):139–146PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Feng Y, LoGrasso PV, Defert O, Li R (2016) Rho kinase (ROCK) inhibitors and their therapeutic potential. J Med Chem 59(6):2269–2300PubMedCrossRefPubMedCentralGoogle Scholar
  153. 153.
    Rath N et al (2017) ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth. EMBO Mol Med 9(2):198–218PubMedCrossRefPubMedCentralGoogle Scholar
  154. 154.
    Timpson P et al (2011) Spatial regulation of RhoA activity during pancreatic cancer cell invasion driven by mutant p53. Cancer Res 71(3):747–757PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Guerra FS, de Oliveira RG, Fraga CAM, Mermelstein CS, Fernandes PD (2017) ROCK inhibition with Fasudil induces beta-catenin nuclear translocation and inhibits cell migration of MDA-MB 231 human breast cancer cells. Sci Rep 7(1):13723PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA (2002) Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 3(5):349PubMedCrossRefPubMedCentralGoogle Scholar
  157. 157.
    Orimo A et al (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121(3):335–348PubMedCrossRefPubMedCentralGoogle Scholar
  158. 158.
    Albrengues J et al (2014) LIF mediates proinvasive activation of stromal fibroblasts in cancer. Cell Rep 7(5):1664–1678PubMedCrossRefPubMedCentralGoogle Scholar
  159. 159.
    Skobe M, Fusenig NE (1998) Tumorigenic conversion of immortal human keratinocytes through stromal cell activation. Proc Natl Acad Sci 95(3):1050–1055PubMedCrossRefPubMedCentralGoogle Scholar
  160. 160.
    Strutz F et al (2000) Basic fibroblast growth factor expression is increased in human renal fibrogenesis and may mediate autocrine fibroblast proliferation. Kidney Int 57(4):1521–1538PubMedCrossRefPubMedCentralGoogle Scholar
  161. 161.
    Surowiak P et al (2006) Stromal myofibroblasts in breast cancer: relations between their occurrence, tumor grade and expression of some tumour markers. Folia Histochem Cytobiol 44(2):111–116PubMedPubMedCentralGoogle Scholar
  162. 162.
    Graizel D, Zlotogorski-Hurvitz A, Tsesis I, Rosen E, Kedem R, Vered M (2019) Oral cancer-associated fibroblasts predict poor survival: systematic review and meta-analysis. Oral DisGoogle Scholar
  163. 163.
    Son GM, Kwon M-S, Shin D-H, Shin N, Ryu D, Kang C-D (2019) Comparisons of cancer-associated fibroblasts in the intratumoral stroma and invasive front in colorectal cancer. Medicine (Baltimore) 98(18):e15164CrossRefGoogle Scholar
  164. 164.
    Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6(5):392–401PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Gaggioli C et al (2007) Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat Cell Biol 9(12):1392–1400PubMedCrossRefPubMedCentralGoogle Scholar
  166. 166.
    Daubriac J et al (2017) The crosstalk between breast carcinoma-associated fibroblasts and cancer cells promotes RhoA-dependent invasion via IGF-1 and PAI-1. Oncotarget 9(12):10375–10387PubMedPubMedCentralGoogle Scholar
  167. 167.
    Sanz-Moreno V et al (2011) ROCK and JAK1 signaling cooperate to control actomyosin contractility in tumor cells and stroma. Cancer Cell 20(2):229–245PubMedCrossRefPubMedCentralGoogle Scholar
  168. 168.
    Augsten M (2014) Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment. Front Oncol 4:62PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Cai J et al (2012) Fibroblasts in omentum activated by tumor cells promote ovarian cancer growth, adhesion and invasiveness. Carcinogenesis 33(1):20–29PubMedCrossRefPubMedCentralGoogle Scholar
  170. 170.
    Giannoni E et al (2010) Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-Mesenchymal transition and cancer Stemness. Cancer Res 70(17):6945–6956PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Henriksson ML et al (2011) Colorectal cancer cells activate adjacent fibroblasts resulting in FGF1/FGFR3 Signaling and increased invasion. Am J Pathol 178(3):1387–1394PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Jia C-C et al (2013) Cancer-associated fibroblasts from hepatocellular carcinoma promote malignant cell proliferation by HGF secretion. PLoS One 8(5):e63243PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Gascard P, Tlsty TD (2016) Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev 30(9):1002–1019PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Malik R, Lelkes PI, Cukierman E (2015) Biomechanical and biochemical remodeling of stromal extracellular matrix in cancer. Trends Biotechnol 33(4):230–236PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Zhai J et al (2003) Direct interaction of focal adhesion kinase with p190RhoGEF. J Biol Chem 278(27):24865–24873PubMedCrossRefPubMedCentralGoogle Scholar
  176. 176.
    Provenzano PP, Keely PJ (2011) Mechanical signaling through the cytoskeleton regulates cell proliferation by coordinated focal adhesion and Rho GTPase signaling. J Cell Sci 124(8):1195–1205PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Ibbetson SJ, Pyne NT, Pollard AN, Olson MF, Samuel MS (2013) Mechanotransduction pathways promoting tumor progression are activated in invasive human squamous cell carcinoma. Am J Pathol 183(3):930–937PubMedCrossRefPubMedCentralGoogle Scholar
  178. 178.
    Parkin A, Man J, Timpson P, Pajic M (2019) Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy. The FEBS Journal 286(18):3510–3539PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Anderson KG, Stromnes IM, Greenberg PD (2017) Obstacles posed by the tumor microenvironment to T cell activity: a case for synergistic therapies. Cancer Cell 31(3):311–325PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Jiang H et al (2016) Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med 22(8):851–860PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Johan MZ, Samuel MS (2019) Rho–ROCK signaling regulates tumor-microenvironment interactions. Biochem Soc Trans 47(1):101–108PubMedCrossRefPubMedCentralGoogle Scholar
  182. 182.
    Smith A, Bracke M, Leitinger B, Porter JC, Hogg N (2003) LFA-1-induced T cell migration on ICAM-1 involves regulation of MLCK-mediated attachment and ROCK-dependent detachment. J Cell Sci 116(15):3123–3133PubMedCrossRefPubMedCentralGoogle Scholar
  183. 183.
    Heasman SJ, Ridley AJ (2010) Multiple roles for RhoA during T cell transendothelial migration. Small GTPases 1(3):174–179PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Zhang S et al (2014) Gene targeting RhoA reveals its essential role in coordinating mitochondrial function and Thymocyte development. J Immunol 193(12):5973–5982PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Tharaux P-L et al (2003) Rho kinase promotes Alloimmune responses by regulating the proliferation and structure of T cells. J Immunol 171(1):96–105PubMedCrossRefPubMedCentralGoogle Scholar
  186. 186.
    Zhu M et al (2011) Role of Rho kinase isoforms in murine allergic airway responses. Eur Respir J 38(4):841–850PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Biswas PS et al (2010) Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice. J Clin Invest 120(9):3280–3295PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P (2017) Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 14(7):399–416PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Zandi S et al (2015) ROCK-isoform-specific polarization of macrophages associated with age-related macular degeneration. Cell Rep 10(7):1173–1186PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Guiet R et al (2011) The process of macrophage migration promotes matrix metalloproteinase-independent invasion by tumor cells. J Immunol 187(7):3806–3814PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Goethem EV, Poincloux R, Gauffre F, Maridonneau-Parini I, Cabec VL (2010) Matrix architecture dictates three-dimensional migration modes of human macrophages: differential involvement of proteases and Podosome-like structures. J Immunol 184(2):1049–1061PubMedCrossRefPubMedCentralGoogle Scholar
  192. 192.
    Georgouli M et al (2019) Regional activation of Myosin II in cancer cells drives tumor progression via a secretory cross-talk with the immune microenvironment. Cell 176(4):757–774.e23PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Von Hoff DD et al (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369(18):1691–1703CrossRefGoogle Scholar
  194. 194.
    Conroy T et al (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364(19):1817–1825PubMedCrossRefPubMedCentralGoogle Scholar
  195. 195.
    Notta F et al (2016) A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature 538(7625):378–382PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA (2012) The pancreas cancer microenvironment. Clin Cancer Res 18(16):4266–4276PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Vonlaufen A et al (2010) Isolation of quiescent human pancreatic stellate cells: a promising in vitro tool for studies of human pancreatic stellate cell biology. Pancreatology 10(4):434–443PubMedCrossRefPubMedCentralGoogle Scholar
  198. 198.
    Öhlund D et al (2017) Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp MedGoogle Scholar
  199. 199.
    Whatcott CJ, Ng S, Barrett MT, Hostetter G, Von Hoff DD, Han H (2017) Inhibition of ROCK1 kinase modulates both tumor cells and stromal fibroblasts in pancreatic cancer. PLoS One 12(8):e0183871PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Masamune A, Kikuta K, Satoh M, Satoh K, Shimosegawa T (2003) Rho kinase inhibitors block activation of pancreatic stellate cells. Br J Pharmacol 140(7):1292–1302PubMedPubMedCentralCrossRefGoogle Scholar
  201. 201.
    Andreas S, Vasiliki G, Maria L, Zacharia Lefteris C, Triantafyllos S (2019) Collagen content and extracellular matrix cause cytoskeletal remodelling in pancreatic fibroblasts. J R Soc Interface 16(154)Google Scholar
  202. 202.
    Kaneko K, Satoh K, Masamune A, Satoh A, Shimosegawa T (2002) Expression of ROCK-1 in human pancreatic cancer: its Down-regulation by Morpholino Oligo antisense can reduce the migration of pancreatic cancer cells in vitro. Pancreas 24(3):251–257PubMedCrossRefPubMedCentralGoogle Scholar
  203. 203.
    Ivanov AI, Samarin SN, Bachar M, Parkos CA, Nusrat A (2009) Protein kinase C activation disrupts epithelial apical junctions via ROCK-II dependent stimulation of actomyosin contractility. BMC Cell Biol 10(1):36PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Rath N, Kalna G, Clark W, Olson MF (2016) ROCK signalling induced gene expression changes in mouse pancreatic ductal adenocarcinoma cells. Sci Data 3:160101PubMedPubMedCentralCrossRefGoogle Scholar
  205. 205.
    Hingorani SR et al (2003) Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4(6):437–450PubMedCrossRefPubMedCentralGoogle Scholar
  206. 206.
    Fujimura K, Choi S, Wyse M, Strnadel J, Wright T, Klemke R (2015) Eukaryotic translation initiation factor 5A (EIF5A) regulates pancreatic cancer metastasis by modulating RhoA and Rho-associated kinase (ROCK) protein expression levels. J Biol Chem 290(50):29907–29919PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Vennin C, Murphy KJ, Morton JP, Cox TR, Pajic M, Timpson P (2018) Reshaping the tumor Stroma for treatment of pancreatic cancer. Gastroenterology 154(4):820–838PubMedCrossRefGoogle Scholar
  208. 208.
    Heid I et al (2011) Early requirement of Rac1 in a mouse model of pancreatic cancer. Gastroenterology 141(2):719–730.e7PubMedCrossRefGoogle Scholar
  209. 209.
    Porazinski S et al (2016) EphA2 drives the segregation of Ras-transformed epithelial cells from normal neighbors. Curr Biol 26(23):3220–3229PubMedCrossRefGoogle Scholar
  210. 210.
    Hogan C et al (2009) Characterization of the interface between normal and transformed epithelial cells. Nat Cell Biol 11(4):460–467PubMedCrossRefGoogle Scholar
  211. 211.
    Padera TP, Stoll BR, Tooredman JB, Capen D, di Tomaso E, Jain RK (2004) Cancer cells compress intratumour vessels. Nature 427(6976):695PubMedCrossRefPubMedCentralGoogle Scholar
  212. 212.
    Beil M et al (2003) Sphingosylphosphorylcholine regulates keratin network architecture and visco-elastic properties of human cancer cells. Nat Cell Biol 5(9):803PubMedCrossRefPubMedCentralGoogle Scholar
  213. 213.
    Paszek MJ, Weaver VM (2004) The tension mounts: mechanics meets morphogenesis and malignancy. J Mammary Gland Biol Neoplasia 9(4):325–342PubMedCrossRefPubMedCentralGoogle Scholar
  214. 214.
    Paszek MJ et al (2005) Tensional homeostasis and the malignant phenotype. Cancer Cell 8(3):241–254PubMedCrossRefPubMedCentralGoogle Scholar
  215. 215.
    Calvo F et al (2013) Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat Cell Biol 15(6):637–646PubMedCrossRefPubMedCentralGoogle Scholar
  216. 216.
    Patel RA et al (2012) RKI-1447 is a potent inhibitor of the rho-associated ROCK kinases with anti-invasive and antitumor activities in breast cancer. Cancer Res 72(19):5025–5034PubMedPubMedCentralCrossRefGoogle Scholar
  217. 217.
    Patel RA, Liu Y, Wang B, Li R, Sebti SM (2014) Identification of novel ROCK inhibitors with anti-migratory and anti-invasive activities. Oncogene 33(5):550–555PubMedCrossRefPubMedCentralGoogle Scholar
  218. 218.
    Cowey CL, Rathmell WK (2009) VHL gene mutations in renal cell carcinoma: role as a biomarker of disease outcome and drug efficacy. Curr Oncol Rep 11(2):94–101PubMedPubMedCentralCrossRefGoogle Scholar
  219. 219.
    Turcotte S, Desrosiers RR, Béliveau R (2003) HIF-1alpha mRNA and protein upregulation involves Rho GTPase expression during hypoxia in renal cell carcinoma. J Cell Sci 116(Pt 11):2247–2260PubMedCrossRefPubMedCentralGoogle Scholar
  220. 220.
    Kamai T et al (2003) RhoA is associated with invasion and lymph node metastasis in upper urinary tract cancer. BJU Int 91(3):234–238PubMedCrossRefPubMedCentralGoogle Scholar
  221. 221.
    Abe H et al (2014) The rho-kinase inhibitor HA-1077 suppresses proliferation/migration and induces apoptosis of urothelial cancer cells. BMC Cancer 14(1):412PubMedPubMedCentralCrossRefGoogle Scholar
  222. 222.
    Shimizu T et al (2010) C-MYC overexpression with loss of Ink4a/Arf transforms bone marrow stromal cells into osteosarcoma accompanied by loss of adipogenesis. Oncogene 29(42):5687–5699PubMedCrossRefPubMedCentralGoogle Scholar
  223. 223.
    Takahashi N et al (2019) ROCK inhibition induces terminal adipocyte differentiation and suppresses tumorigenesis in Chemoresistant osteosarcoma cells. Cancer Res 79(12):3088–3099PubMedCrossRefPubMedCentralGoogle Scholar
  224. 224.
    Özdemir BC et al (2014) Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25(6):719–734PubMedPubMedCentralCrossRefGoogle Scholar
  225. 225.
    Rhim AD et al (2014) Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25(6):735–747PubMedPubMedCentralCrossRefGoogle Scholar
  226. 226.
    Laklai H et al (2016) Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat Med 22(5):497–505PubMedPubMedCentralCrossRefGoogle Scholar
  227. 227.
    Vennin C et al (2017) Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. Sci Transl Med 9(384):eaai8504PubMedPubMedCentralCrossRefGoogle Scholar
  228. 228.
    Vennin C, Rath N, Pajic M, Olson MF, Timpson P (2017) Targeting ROCK activity to disrupt and prime pancreatic cancer for chemotherapy. Small GTPases 1–8Google Scholar
  229. 229.
    Chin VT, Vennin C, Timpson P, Pajic M (2017) Effective modulation of stromal signaling through ROCK inhibition: is it all in the timing? Mol Cell Oncol 4(5):e1333973PubMedPubMedCentralCrossRefGoogle Scholar
  230. 230.
    Conway JRW, Warren SC, Timpson P (2017) Context-dependent intravital imaging of therapeutic response using intramolecular FRET biosensors. Methods 128:78–94PubMedCrossRefPubMedCentralGoogle Scholar
  231. 231.
    Conway JRW, Carragher NO, Timpson P (2014) Developments in preclinical cancer imaging: innovating the discovery of therapeutics. Nat Rev Cancer 14(5):314–328PubMedCrossRefPubMedCentralGoogle Scholar
  232. 232.
    Sunyer R et al (2016) Collective cell durotaxis emerges from long-range intercellular force transmission. Science 353(6304):1157–1161PubMedCrossRefPubMedCentralGoogle Scholar
  233. 233.
    Costa-Silva B et al (2015) Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol 17(6):816–826PubMedPubMedCentralCrossRefGoogle Scholar
  234. 234.
    Sadok A et al (2015) Rho kinase inhibitors block melanoma cell migration and inhibit metastasis. Cancer Res 75(11):2272–2284PubMedCrossRefPubMedCentralGoogle Scholar
  235. 235.
    Croghan GA et al (2010) A study of paclitaxel, carboplatin, and bortezomib in the treatment of metastatic malignant melanoma. Cancer 116(14):3463–3468PubMedCrossRefPubMedCentralGoogle Scholar
  236. 236.
    Markovic SN et al (2005) A phase II study of bortezomib in the treatment of metastatic malignant melanoma. Cancer 103(12):2584–2589PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Sean Porazinski
    • 1
    • 2
  • Ashleigh Parkin
    • 1
  • Marina Pajic
    • 1
    • 2
    Email author
  1. 1.Personalised Cancer Therapeutics LabThe Kinghorn Cancer CentreSydneyAustralia
  2. 2.Faculty of Medicine, St Vincent’s Clinical SchoolUniversity of NSWSydneyAustralia

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