Many key characteristics of the tissue microenvironment are fundamentally changed in cancer to produce the tumour microenvironment. It is becoming increasingly clear that these changes arise as a result of tumours co-opting features of the tissue microenvironment to facilitate their growth.
Our research seeks to identify the mechanisms by which the tumour microenvironment impacts on the initiation and progression of cancers. Conversely, we are also studying how cancers act to remodel their microenvironments, resisting the body’s attempt to normalise them.
The Rho-ROCK signalling pathway is known to regulate the contractility of the cellular actomyosin cytoskeleton to promote tumour cell migration and invasion. Less well-understood is its role in remodelling the tissue microenvironment. We have discovered that activation of the Rho-ROCK signalling pathway within the skin causes over-production and abnormal remodelling of collagen. The resulting increase in tissue density disrupts normal tissue homeostasis and promotes tumourigenesis. We are now working to determine how signalling through the Rho-ROCK pathway brings about these changes, and the impact on human cancers.
Current research projects
- The mechanism of tumour promotion by the Rho-ROCK signalling pathway and its function in mechano-reciprocity
- How does the Rho-ROCK pathway generate a permissive tumour microenvironment?
- How is the Rho-ROCK pathway regulated during wound healing?
- Identifying novel negative regulators of mechano-reciprocity.
Learn more about our research.
S. T. Boyle, J. Kular, M. Nobis, A. Ruszkiewicz, P. Timpson and M. S. Samuel. "Acute compressive stress activates RHO/ROCK-mediated cellular processes". Small GTPases (In Press, 2018).
N. Rath, J. P. Morton, L. Julian, L. Helbig, S. Kadir, E. J. McGhee, K. I. Anderson, G. Kalna, M. Mullin, A. V. Pinho, I. Rooman, M. S. Samuel and M. F. Olson. "ROCK signaling promotes collagen remodeling to facilitate invasive pancreatic ductal adenocarcinoma tumor cell growth". EMBO Mol Medicine 9(2):198-218 (2017).
M. S. Samuel, N. Rath, S. F. Masre, S. T. Boyle, D. A. Greenhalgh, M. Kochetkova, S. Bryson, D. Stevenson and M. F. Olson. "Tissue-selective expression of a conditionally-active ROCK2-estrogen receptor fusion protein". Genesis 54(12):636-646 (2016).
S. T. Boyle and M. S. Samuel. "Mechano-reciprocity is maintained between physiological boundaries by tuning signal flux through the Rho-associated protein kinase". Small GTPases 7(3): 139-146 (2016).
J. Kular, K. G. Scheer, N. T. Pyne, A. H. Allam, A. Pollard, A. Magenau, R. Wright, N, Kolesnikoff, P. A. Moretti, L. Wullkopf, F. Stomski, A. J. Cowin, J. M. Woodcock, M. A. Grimbaldeston, S. M. Pitson, P. Timpson, H. S. Ramshaw, A. F. Lopez and M. S. Samuel. "A negative regulatory mechanism involving 14-3-3ζ limits signaling downstream of ROCK to regulate tissue stiffness in epidermal homeostasis." Developmental Cell 35(6): 759-774 (2015).
K. H. Yip, N. Kolesnikoff, C. Yu, N. Hauschild, H. Taing, L. Biggs, D. Goltzman, P. A. Gregory, P. H. Anderson, M. S. Samuel, S. J. Galli, A. F. Lopez and M. A. Grimbaldeston. "Mechanisms of vitamin D3 metabolite repression of IgE-dependent mast cell activation." J Allergy Clin Immunol 133: 1356-1364.e14. (2014).
S. J. Ibbetson, N. T. Pyne, A. N. Pollard, M. F. Olson, M. S. Samuel. "Mechanotransduction Pathways Promoting Tumor Progression Are Activated in Invasive Human Squamous Cell Carcinoma." Am J Pathol. 183: 931-938 (2013).
M. S. Samuel , J. I. Lopez, E. J. McGhee, D. R. Croft, D. Strachan, P. Timpson, J. Munro, E. Schroder, J. Zhou, V. G. Brunton, N. Barker, H. Clevers, O. J. Sansom, K. I. Anderson, V. M. Weaver and M. F. Olson. "Actomyosin-mediated cellular tension drives increased tissue stiffness and beta-catenin activation to induce epidermal hyperplasia and tumor growth." Cancer Cell 19: 776-791. (2011).