Tumour Microenvironment Laboratory
Many key characteristics of the tissue microenvironment are fundamentally changed in cancer, yielding the tumour microenvironment. Some of these changes arise as a result of tumours co-opting and modifying features of the tissue microenvironment to facilitate their growth.
Our research seeks to identify the mechanisms by which tumours 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 ROCK kinase causes over-production and abnormal remodelling of collagen and other ECM components in many tissues. The resulting increase in tissue density disrupts normal tissue homeostasis and promotes tumourigenesis. We research the mechanismsby which ROCK regulates these processes in both health and disease, with a focus on cancer.
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.
- How do tumours co-opt cancer-associated fibroblasts for tumorigenesis?
Learn more about our research.
S. T. Boyle, V. Poltavets, J. Kular, N. T. Pyne, J. J. Sandow, A. C. Lewis, K. J. Murphy, N. Kolesnikoff, P. A. B. Moretti, M. N. Tea, V. Tergaonkar, P. Timpson, S. M. Pitson, A. I. Webb, R. J. Whitfield, A. F. Lopez, M. Kochetkova and M. S. Samuel. "ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism". Nature Cell Biology 22(7):882-895 (2020).
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 11(5):354-370 (2020).
M. Z. Johan and M. S. Samuel. "Rho-ROCK signaling regulates tumour-microenvironment interactions". Biochem. Soc. Trans. 41(1):101-108 (2019).
H. A. Neubauer, M. N. Tea, J. R. Zebol, B. L. Gliddon, C. Stefanidis, P. A. B. Moretti, M. R. Pitman, M. Costabile, J. Kular, B. W. Stringer, B. W. Day, M. S. Samuel, C. S. Bonder, J. A. Powell and S. M. Pitson. Cytoplasmic dynein regulates the subcellular localization of sphingosine kinase 2 to elicit tumor-suppressive functions in glioblastoma. Oncogene 38(8):1151-1165 (2019).
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).
A. S. Cazet, M. N. Hui, B. L. Elsworth, S. Z. Wu, D. Roden, C. L. Chan, J. N. Skhinas, R. Collot, J. Yang, K. Harvey, M. Z. Johan, C. Cooper, R. Nair, D. Herrmann, A. McFarland, N. Deng, M. Ruiz-Borrego, F. Rojo, J. M. Trigo, S. Bezares, R. Caballero, E. Lim, P. Timpson, S. O'Toole, D. N. Watkins, T. R. Cox, M. S. Samuel, M. Martín and A. Swarbrick. Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer. Nat. Commun. 9(1):2897 (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).
C. Vennin, V. T. Chin, S. C.Warren, M. C. Lucas, D. Herrmann, A. Magenau, P. Melenec, S. N. Walters, G. Del Monte-Nieto, J. R. Conway, M. Nobis, A. H. Allam, R. A. McCloy, N. Currey, M. Pinese, A. Boulghourjian, A. Zaratzian, A. A. Adam, C. Heu, A. M. Nagrial, A. Chou, A. Steinmann, A. Drury, D. Froio, M. Giry-Laterriere, N. L. Harris, T. Phan, R. Jain, W. Weninger, E. J. McGhee, R. Whan, A. L. Johns, J. S. Samra, L. Chantrill, A. J. Gill, M. Kohonen-Corish, R. P. Harvey, A. V. Biankin; Australian Pancreatic Cancer Genome Initiative (APGI), T. R. Evans, K. I. Anderson, S. T. Grey, C. J. Ormandy, D. Gallego-Ortega, Y. Wang, M. S. Samuel, O. J. Sansom, A. Burgess, T. R. Cox, J. P. Morton, M. Pajic and Timpson P. Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. Sci Transl Med. 9(384):eaai8504 (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).