The breakdown of epithelial tissue architecture and function greatly contribute to the severe damage of organs in different types of diseases including cancer.
Physical forces are a key determinant of tissue architecture controlling also cellular behaviours that range from the differentiation of stem cells to cell transformation and cancer invasion. We have made significant progress in understanding the mechanisms involved in capacity of the cells to generate forces and the regulation of epithelial organization. We now are using this knowledge to understand how dysregulation of tissue mechanics contributes to the loss of tissue architecture and organ function.
Epithelial architecture and the establishment of cell polarity. A key property of epithelial tissue architecture is the presence of an apical-basal polarity, which constitutes the basis for its function as a barrier.
Polarity has been extensively characterised in terms of the different lipids and proteins that are spatially segregated in polarised cells and much is known about the signalling pathways that support polarity once it has been established. However, we do not yet understand how the process of polarisation is initiated. Based on our recent advances in the biomechanical control of cell signalling (Priya and Gomez, PloS Comp Biol 2017 and Priya et al, Nature Cell Biology, 2015) and by using super resolution microscopy and computational modelling our aim is to identify the symmetry breaking mechanisms that contribute to the specification of apico-basal domains in the epithelial tissue.
Role of the metabolic microenvironment in the loss of epithelial architecture and cancer progression. The tumour microenvironment profoundly influences the decision of tumour cells to become invasive. Hypoxia and acidosis are common features in advanced solid tumours and their presence predicts poor outcomes. Hypoxia correlates with an increased occurrence of metastasis while acidosis increases tumour dysplasia. How these metabolic changes in the tumour microenvironment act to promote tumour spread is yet to be understood.
We have recently identified how the cytoskeleton of the cell can be mechanically altered to potentially promote cancer cell invasion through the process of oncogenic cell extrusion. Extrusion occurs when minorities of transformed tumour cells are expelled from their tissues of origin, causing tumours to proliferate and invade. We discovered that extrusion is a biomechanical process (Wu et al, Nature Cell Biology, 2014) and more recently, we have found it to be exacerbated when cells are exposed to acidosis or hypoxia. Now, my lab is investigating how by modulating the actin cytoskeleton, the microenvironment alters tumour cell mechanics promoting cell extrusion and thereby initiating tumour invasion.
Tissue regeneration in response to epithelial injury. Although some aspects of epithelial tissue regeneration have been elucidated, it remains unclear how regenerative responses are triggered, maintained and terminated to produce the exact number of cells required for tissue repair. Understanding how epithelial cells tightly control their proliferation rates within the tissue in response to injury has profound implications for regenerative medicine and cancer treatment.
Efficient repair requires a coordinated response of cells surrounding the sites of damage. In the epithelia, this is influenced by the capacity of the cells to exert physical forces on their neighbours. By combining mathematical modelling and wet-lab experimentation, we have shown how cell mechanics coordinates collective cellular morphological re-arrangements required to preserve epithelial barrier function in response to injury. We now want to discover how alteration in epithelial tissue mechanics contributes to cell proliferation.
Positions for PhD and Honor’s students are open in this laboratory. Prospective postdocs please contact Guillermo Gomez if you are interested in joining his lab and also if you are in your final year of a PhD. Enquires from candidates with a strong background in (any of) the following areas: Physical Biology, Biophysics, computer science, stem cell research, mechanobiology and super resolution microscopy are very welcome. Positions may be dependent on the time of the year and funding.
- Priya R*, Gomez GA*, Budnar S, Acharya BR, Czirok A, Yap AS, Neufeld Z. Bistable front dynamics in a contractile medium: Travelling wave fronts and cortical advection define stable zones of RhoA signaling at epithelial adherens junctions. PLoS Computational Biology 2017 13 (3), e1005411 *Co-first authors
- Priya R*, LiangX, Teo JL, Duszyc K., Yap AS and Gomez GA*. "ROCK1 but not ROCK2 contributes to RhoA signaling and NMIIA mediated contractility at the epithelial zonula adherens". Molecular Biology of the Cell 2017. 28(1):12-20. *Corresponding authors
- Coburn L*, Lopez H, Caldwell BJ, Moussa E, Yap C, Priya R, Noppe A, Roberts AP, Lobaskin V, Yap AS, Neufeld Z, Gomez GA*. Contact inhibition of locomotion and mechanical cross-talk between cell-cell and cell-substrate adhesion determines the pattern of junctional tension in epithelial cell aggregates. Molecular Biology of the Cell. 2016 27(22):3436-3448 *Corresponding authors
- Michael M, Meiring JC, Acharya BR, Matthews DR, Verma S, Han SP, Hill MM, Parton RG, Gomez GA, Yap AS. Coronin 1B Reorganizes the Architecture of F-Actin Networks for Contractility at Steady-State and Apoptotic Adherens Junctions. Developmental Cell. 2016 Apr 4;37(1):58-71.
- Priya R, Gomez GA*, Budnar S, Verma S, Cox HL, Hamilton NA, Yap AS*. Feedback regulation through myosin II confers robustness on RhoA signalling at E-cadherin junctions. Nature Cell Biology. 2015 Oct;17(10):1282-93. *Corresponding authors
- Gomez GA*, McLachlan RW, Yap AS*., et. al. An RPTPα/Src Family Kinase /Rap1 signaling module Molecular Biology of the Cell. 2015. 26:1249. * Corresponding authors.
- Caldwell BJ, Lucas C, Kee AJ, Gaus K, Gunning PW, Hardeman EC, Yap AS* and Gomez GA*. Tropomyosin isoforms support actomyosin biogenesis to generate contractile tension at the epithelial zonula adherens. Cytoskeleton 2014; 71:663. *Corresponding authors.
- Wu SK, Gomez GA*, Yap AS*, et. al. Cortical F-actin stabilization generates apical-lateral patterns of junctional contractility that integrate cells into epithelia. Nature Cell Biology. 2014 Feb;16(2):167. *Corresponding authors.
- Priya R, Yap AS, Gomez GA. E-cadherin supports steady-state Rho signaling at the epithelial zonula adherens. Differentiation 2013. Oct;86(3):133.
- Ratheesh A.*, Gomez GA*, Priya R, Verma S, Kovacs EM, Jiang K, Brown NH, Akhmanova A, Stehbens SJ, Yap AS. “Centralspindlin and α-catenin regulate Rho signalling at the epithelial zonula adherens”. Nature Cell Biology. 2012 14(8):818-28.* co-first author.