The mechanical properties of tissues play a vital role in maintaining health. Elastic fibres, for example, allow tissues such the skin, lungs and blood vessels to deform and recoil whilst the giant protein titin plays a major role in elasticity of the heart. During ageing these tissues become stiffer, contributing significantly to patient morbidity and mortality. Using nano-mechanical, micro-mechanical, biochemical and proteomic analyses of aged and young tissue samples my research aims to characterise the fundamental molecular changes in elastic proteins which underlie age-related changes in tissue elasticity.
The lab focuses on exploring how the trafficking of receptor tyrosine kinases (RTKs) from and to the plasma membrane can elicit specific cellular responses. We use a highly multidisciplinary approach named ‘functional proteomics’, which integrates quantitative Mass Spectrometry (MS)-based proteomics, bioinformatics analysis, functional assays and imaging techniques. Our research aims at uncovering the molecular mechanisms underlying the intracellular trafficking of RTKs, resultant signaling specificity, and downstream outputs during development and cancer progression. The final goal hereby is to identify and characterize proteins with key roles in RTK signaling and trafficking that can be targeted for intervention in human diseases.
During development, cells transition from a progenitor state to differentiation with defined timing, or to quiescence from which they may be reactivated. Understanding how such transitions and their timing are regulated is key in understanding how tissues are built, maintained, repaired or subverted in disease.
In recent years, our understanding of how cells make cell state transitions has been transformed by the application of single cell molecular technology that revealed a large degree of non-genetic heterogeneity in seemingly homogeneous populations of cells. In neural progenitors, single cell imaging with unstable reporters has revealed asynchronous pulsatile fluctuations in regulatory gene expression, which is masked by static measurements of population averages. Thus, cell fate transitions may not be driven simply by genes being turned on or off, but by a change in the dynamics of gene expression for example, from fluctuating or pulsatile expression to a more stable state.
Cells in every organism can process external signals thanks to clever systems that enable the information encoded by the signals to be transmitted inside the cell. These systems, also known as pathways, allow healthy cells to communicate with each other and to respond to changes in their environment. Consequently, diseases can occur when these networks are disrupted or inappropriately stimulated. For example, we have identified a pathway that causes cancer cells to grow and divide in an uncontrolled manner, forming a tumour. We have also found that a similar pathway is responsible for instructing brain cells to die. The importance of this finding is highlighted by the fact that excessive loss of brain cells is associated with neurological disorders characteristic of age-related degenerative diseases or associated with brain injury. Based on these initials findings my laboratory is interested in understanding how pathways transmit specific information within the cells, so that strategies to repair networks of signal transduction can be developed to treat diseases.
The tissues of our bodies are extremely complicated at the cellular level, comprising different types of cells arranged with precise geometry. Within this complex system, the direction in which a cell divides is a crucial tool used to shape tissues and determine cell fate. Defects in division orientation have lethal consequences: they cause failures in embryonic development and are associated with cancer.
To coordinate cell division across a tissue, cells must be able to “read” their external cellular environment and orient their division accordingly. The mechanisms that control this remain unclear, but we know that cues from the extracellular matrix play a vital role. These cues must be fed to a cellular structure called the mitotic spindle, the positioning of which determines cell division orientation. Understanding the mechanisms used by the cell to correctly position the spindle is a key focus of our lab. In particular, we are investigating how molecular forces are balanced inside the cell to position the mitotic spindle and how these internal mechanisms are linked to the external cellular environment in order to coordinate spindle orientation across a tissue.
Mr Mohammed Absar
Clinical Director of the Greater Manchester Cancer Breast Pathway Board
Dr Ciara O’Brien is a Consultant Medical Oncologist with translational and clinical research interest in targeted therapies for early and advanced breast cancer.
Dr Ciara O’Brien graduated from University College London Medical School in 2003. During her undergraduate training she undertook research investigating the genomics of benign to malignant progression in apocrine breast cancer (supervisor Professor Sunil R Lakhani).
She was awarded an AACR Scholar in Training Award in 2009 for work leading to the award of PhD from University of Manchester in 2011. Her PhD carried out within the Breast Biology group, CRUK Manchester Institute (supervisors Dr Sacha Howell and Dr Rob Clarke) investigated cancer stem cells and stem cell pathways as drivers of resistance to endocrine therapy in breast cancer.
Dr Ciara O’Brien completed specialist training at the Christie Hospital, Manchester and obtained her CCT in Medical Oncology in 2016. She subsequently undertook a post- CCT fellowship in Experimental Cancer Medicine at the Christie Hospital/University of Manchester with a focus on translational research, precision oncology and early phase clinical trials in breast cancer.
Dr Ciara O’Brien was appointed as a trainee member of NCRI Breast clinical trials subgroup between 2015 and 2016. She is also an active member of the National Trainee Research Collaborative in Breast Cancer Surgery and Oncology.