Tumour Microenvironment Laboratory
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 remodel their microenvironments to promote tumour progression, with a view to uncovering new approaches to interfering with this process.
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 and other ECM components. 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 their impact on human cancers.
Current research projects
- The molecular mechanisms by which the Rho-ROCK pathway promotes enhanced mechano-reciprocity and tumour progression
- How does the Rho-ROCK pathway generate a tumour-permissive immune microenvironment?
- How is the Rho-ROCK pathway regulated during wound healing and cancer progression?
- 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, 2019).
M. Z. Johan and M. S. Samuel. "Rho-ROCK signaling regulates tumour-microenvironment interactions". Biochem. Soc. Trans. 41(1):101-108 (2018).
V. Poltavets, M. Kochetkova, S. M. Pitson and M. S. Samuel. "The role of the extra-cellular matrix and its molecular and cellular regulators in cancer cell plasticity". Frontiers in Oncology 8:431 (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).