Revealing vulnerabilities of the microtube network and inter-cellular communication in gliomas through mechanistic computational modelling

Precision Medicine Project - Revealing vulnerabilities of the microtube network and inter-cellular communication in gliomas through mechanistic computational modelling

Supervisor(s): Dr Dirk Sieger, Prof Steven Pollard & Dr Xiao Fu (University of Glasgow)
Centre/Institute: Centre for Discovery Brain Sciences

Background:

Despite our improved understanding of how genomic alterations fuel the development of glioblastomas (GBM), patients rarely benefit from existing treatments. There remains an unmet clinical need for the discovery of novel therapeutic targets. Recent studies demonstrated that the microtube network formed by glioma cells can mediate efficient long-distance communications between cells and enhance their collective resilience to therapeutic challenges. Furthermore, there is growing evidence that components of the tumour microenvironment (TME) such as microglia and macrophages communicate with glioma cells to delineate disease progression. Nevertheless, how traits and behaviours of glioma cells and other cells in the TME shape the dynamic formation of microtube networks remains incompletely delineated. Crucially, clarification of key cellular and molecular mechanisms has the potential to reveal vulnerabilities of glioma tumorigenesis and lead to the discovery of novel therapeutic targets.

From a theoretical perspective, a range of biological processes spanning varying length and time scales collectively sculpt the glioma microtube networks. Glioma cells’ states and behaviours, such as proliferation and migration, influence the density and spatial distribution of cells. Processes of cellular protrusion, such as extension, retraction, branching, and connection impact the frequency of microtube connections between cells. These biological processes, when integrated in space and time, inevitably results in a complex system that is challenging to study based solely on experimental and clinical analyses. Mathematical and computational modelling is playing an increasingly important role in unpicking mechanisms of complex biological systems, as exemplified by previous studies by us and others in the context of tumour evolution [Fu, et al. Nat Ecol Evol (2022)]. 

Aims

This project seeks to dissect the cancer-intrinsic and –extrinsic mechanisms driving the formation of glioma microtube networks and identify key vulnerabilities to target, by integrating our multi-disciplinary expertise in pre-clinical experimental modelling (DS), neural stem cells and lineage reprogramming (SP), and computational modelling (XF).

  1. Aim 1 is to develop a computational model to simulate the formation of glioma microtube networks and screen perturbation strategies.

    The student will develop a model to computationally describe encode glioma cell behaviours and processes of cellular protrusion with XF’s lab. Extensive parameter exploration will be performed to characterise and categorise network phenotypes that result from different combinations of model parameters. Subsequently, simulated phenotypes in two dimensions (2D) will be compared with those in 2D colony formation assays using different glioma stem cell lines in DS’s lab. Next, the model will be used to predict the consequences of in silico perturbations of biological processes, or an “in silico drug screen”. Those shown to disrupt the integrity of the microtube network will be tested experimentally. 

  2. Aim 2 is to extend the computational model to investigate the impact of the TME on microtube network formation.

    The student will implement the computational model in three dimensions (3D) with XF’s lab and further encode biological components and processes such as microglia and their interactions with glioma cells. Simulations realised in 3D will predict the (dis)similarity between 2D and 3D, which can be experimentally validated by comparing 2D cell cultures and spheroid or organoid assays of glioma tumorigenesis with DS’s lab. Alternative hypotheses on the role of microglia on glioma microtube can be tested in silico, with predicted microtube network organisation and spatial distribution of microglia compared with observations from in vivo experiments using zebrafish models.

  3. Aim 3 is to link cellular mechanisms shaping dynamic microtube formation with transcriptional signatures in patient single-cell RNA sequencing data.

    The student will access and analyse already curated patient single-cell RNA sequencing (sc-RNAseq) data with SP’s lab. Of particular interest, key cellular and molecular mechanisms underpinning the formation of glioma microtube network revealed in Aim 1 and Aim 2 will be explored in sc-RNAseq. For example, glioma cell migratory behaviours in the computational model could be linked to the score of epithelial-to-mesenchymal transition. The computationally suggested role of microglia through simulations could be linked to sc-RNAseq via ligand-receptor analysis.

    Overall, the project will improve our understanding of the vulnerabilities of glioma microtube networks, identify novel ways to stratify patients, and accelerate the discovery of therapeutic targets.

Training outcomes

At the end of the project, the student will be equipped with multi-disciplinary knowledge and skillsets:

  • With DS’s lab: glioma and microglia biology, in vitro and in vivo experiments, bioimage analysis
  • With SP’s lab: cancer stem cell biology, single-cell transcriptomics, gene therapy
  • With XF’s lab: Mathematical biology, computational modelling, data science

Apply Now

Click here to Apply Now

  • The deadline for 25/26 applications is Monday 13th January 2025
  • Applicants must apply to a specific project. Please ensure you include details of the project on the Recruitment Form below, which you must submit to the research proposal section of your EUCLID application. 
  • Please ensure you upload as many of the requested documents as possible, including a CV, at the time of submitting your EUCLID application.  

 

Q&A Sessions

Supervisor(s) of each project will be holding a 30 minute Q&A session in the first two weeks of December. 

If you have any questions regarding this project, you are invited to attend the session on Wednesday 4th December at 9.30am GMT via Microsoft Teams. Click here (link to follow) to join the session.

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