Research Programme Degradation of cellular material is important for the disposal of unwanted organelles, damaged proteins and pathogens. The degradation products can be recycled in the cell as nutrient and energy supply for cell growth. Malfunction of cellular degradation pathways is associated with various diseases. For example, disrupted degradation of cytoplasmic components is linked to neurological disorders meanwhile increased degradation of cellular material is associated with some types of cancers. How is cellular degradation regulated and how does it impact diseases such as aggressive cancers? Degradation of cellular material can take place via the lysosome or proteasome systems. In order to ensure non-random degradation, certain mechanisms exist in the cell to deliver substrates to either system. Autophagy is one such mechanism that involves the formation of a vesicle, termed the autophagosome, which delivers substrates for degradation to the lysosome system. Image The lab is interested in understanding the following questions: Impact of autophagy during the development and survival of glioblastoma cells Autophagy has been implicated in a wide range of disease with its relevance highly context dependent. The lab is particularly interested in understanding how autophagy impacts aggressive cancers, such as glioblastoma multiforme (GBM). Our current studies aim to understand how autophagy can impact the growth and survival of GBM depending on different oncogenic mutations. To do this, we are using a combination of patient-derived GBM cells and animal modelling. Image Figure 1: Autophagy inhibition impedes glioblastoma development in a mouse model. Kaplan-Mieir curve showing the effects of shRNA targeting core ATG proteins used to inhibit autophagy during KRas-induced gliomagenesis.\n Molecular mechanism underlying ATG proteins recruitment to the pre-autophagosome structures In order to tackle autophagy in disease, it would be important to understand its molecular biology. A number of distinct autophagy-related protein (ATG) complexes have been identified. The ATG complexes are essential for the formation of the autophagosome. A number of questions remain unanswered on how these ATG complexes function during autophagy. The lab is particularly interested in understanding how ATG proteins are activated and targeted to pre-autophagosome membranes. To investigate this, the lab utilises affinity purification, CRISPR/Cas9-mediated gene editing, in vitro reconstitution assays of autophagosome formation and fluorescence imaging. Image Figure 2: Proper localisation of ATG proteins is required for autophagy. Formation of punctate structures corresponding to autophagic membranes (middle panel) is essential during autophagy. Mislocalisation of ATG proteins (right panel) abrogates autophagy.\n Identifying key cellular regulators that can be targeted to inhibit autophagy Autophagy can be regulated by a number of upstream signalling pathways that control general cell function. We are interested in identifying cellular players that are particularly deregulated in cancer cells and can be targeted to inhibit autophagy. This article was published on 2024-09-23
