The Butterworth group work on applying synthetic and biological chemistry to study and solve biological problems of relevance to human health. One key theme of this work is the utilisation of the cell’s biological machinery to selectively activate molecules to kill cancer cells with specific mutations, or to selectively reprogram the activity of key immune cells. We have several breast cancer focussed collaborations with biomedical researchers and clinicians at Manchester and beyond. These include projects with funding from the Wellcome Trust (~£5 million seeding drug discovery award, looking at novel kinase inhibitors in TNBC), CRUK and MRC CiC (together ~£400k, looking at novel kinase modulators as immune-oncology agents in TNBC with Katie Finegan).
My research group investigates the mechanisms by which mitogen-activated protein kinases (MAPK) regulate cancer biology and therapeutic response, with a particular focus on triple-negative breast cancer. Using a combination of established pharmacological inhibitors, novel and exclusive pre-clinical mouse models, human samples and in vivo techniques, my group’s central aim is to translate findings at the molecular level into valid therapeutic avenues and/or biomarkers of cancer progression and therapy response. Current projects include studies into ERK5 and MEK5 inhibitors, and further characterisation of the role of ERK5 in inflammatory responses and metastatic spread.
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.
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.
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