Proteostatic regulation of glioblastoma stemness

Lead Research Organisation: Cardiff University
Department Name: School of Biosciences

Abstract

Glioblastoma is the most aggressive type of brain cancer in adults. There is no cure, and most patients die within 15-18 months after diagnosis, even with treatment. Developing effective therapies against glioblastoma is very difficult, because these cancers are made up of a very diverse mixture of different cancer cells. We have found that a type of glioblastoma cells that is more aggressive than other cells from this cancer also contains more proteins than less aggressive glioblastoma cells. We think this allows more aggressive glioblastoma cells to grow quicker which helps these cells to be more aggressive and regrow into new tumours after treatment.

Our project will investigate differences in proteins between more aggressive and less aggressive glioblastoma cells to find new ways for treating glioblastoma by stopping more aggressive cells from growing. We want to understand how protein production is conducted in each glioblastoma cell type, and we will combine different ways of investigating proteins inside glioblastoma cells. This will allow us to study not only the type of proteins being made, but also how they interact with one another and how they are broken down. As part of our project, we will investigate the protein HECTD1 since it controls the factory which makes proteins, called the ribosome. We will test whether HECTD1 helps more aggressive glioblastoma cells to make more protein and therefore helps glioblastomas to grow back after therapy. This may help find new ways of treating glioblastoma. Finally, we are using a new type of microscope for measuring protein amounts inside glioblastoma cell types and this is exciting because this technology has the potential to readily identify more aggressive glioblastoma cells, with increased sensitivity and quicker than ever before. We will test this in human patient material to evaluate its diagnostic/prognostic value. This new technology could help other scientists and clinicians in the future by making it easier to identify and study more aggressive cancer cells.

Technical Summary

GBM progression and recurrence have been linked to persisting cells evading therapy and initiating tumour regrowth (GSCs). Cancer stemness is influenced by the microenvironment, indicating some degree of plasticity between GBM cell populations. Nevertheless, therapeutic targeting of GSC states is likely to help overcome therapy resistance of GBM. Single cell profiling studies have shown that GBM cell populations reflect signatures of neurodevelopmental cell types, indicating that developmental programs are exploited by GBM cells to promote tumour propagation. FGF2 signalling is a developmentally relevant pathway which we have shown regulates GSC maintenance. Further, new published and preliminary data support increased protein content and protein synthesis as key features of GSCs although how these impact on the propagation potential of GBM tumour cells remains unknown. At the core, our project aims to establish how proteostasis and stemness are linked in GBM with the view to identify new therapeutically targetable mechanisms. Our preliminary data strongly suggest the E3 ubiquitin ligase HECTD1 is the nexus between FGF2 signalling and protein synthesis in GSCs. We now aim to provide detailed molecular explanations for the dual role of HECTD1 in FGF2 signalling and in protein synthesis and to establish how these mechanisms impact on GSC stemness. We will use comparative multi-omics analysis of GSCs and NGCs to define a comprehensive molecular signature of the stemness state in GBM and to identify additional candidate targets which may regulate stemness through an effect on proteostasis. Finally, our data supports non-linear optical microscopy for the label-free identification of GSCs and NGCs in situ and we will further build on this method for detecting cancer stem cells without the need for additional labelling in human GBM patient samples, including for live imaging experiments.

Publications

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