“Fixed and cleared fluorescently labelled Human brain organoid grown for 30 days imaged using multiphoton microscopy at the ACRF Cancer Discovery Accelerator Facility. Image generated by Dr. Mariana Oksdath, Tissue architecture and organ Function Laboratory.”
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.