LIMR Cancer: Why and how do brain tumour cells invade ‘mini-brains’?

Summary

Globally, nearly 189,000 people die each year as a result of brain cancer and around 250,000 people are diagnosed with a malignant brain tumour (umbrella name: glioma). No cure is available and the highly-infiltrative growth of gliomas into healthy brain tissue hinders complete surgical resection of the tumour, also complicating precision medicine approaches that are urgently required to prevent tumour recurrence, despite aggressive chemoradiotherapy. One significant challenge is to faithfully study glioma cell migration in 3D in the laboratory. To this end, we have demonstrated that transcriptionally-heterogeneous patient-derived brain cancer cell models (1) spontaneously invade into healthy stem cell-derived ‘mini-brains’, within 48 hours (2). The resultant self-assembling glioma-organoids - hereafter termed ‘assembloids’ - represent a pioneering 3D laboratory assay to study tumour biology in a clinically relevant timeline. Here, we aim to elucidate the molecular basis of the migration routes of glioma cell patches within the ‘mini brains’ under control and malignant network-inducing conditions, which are associated with a change in cell migration behavior (3). We will use gene expression profiling combined with loss- and gain-of-function approaches that will identify genes and proteins that can significantly change glioma cell-organoid cell interactions that either increase or reduce glioma cell motility over time. Ultimately, we aim to identify therapeutic (protein) targets that fuel glioma infiltration, and therefore, may be exploited for developing anti-glioma precision medicine approaches.

Techniques associated with project

Pluripotent stem cell and patient-derived glioma cell culture, (bespoke) self-assembling organoids, gene expression profiling (mRNA-seq), ectopic gene expression, gene knockdown, histology, tissue clearing, immunostaining, qRT-PCR

References

The small molecule KHS101 induces bioenergetic dysfunction in glioblastoma cells through inhibition of mitochondrial HSPD1, Polson S., Kuchler V.B., Abbosh C., Ross E.M., Mathew, R.K., Beard H.A., Chuntharpursat-Bon E., Williams J., Da Silva B., Shao H., Patel A., Davies A.J., Droop A., Griffiths H.B.S., Chumas P., Short S.C., Lorger M., Gestwicki J., Roberts L.D., Bon, R.S. Allison S.J., Zhu S., Markowetz F., Wurdak H. (2018) Science Translational Medicine 15;10(454). pii: eaar2718. doi: 10.1126/scitranslmed.aar2718.

Spontaneous glioblastoma spheroid infiltration of early-stage cerebral organoids models brain tumor invasion, da Silva B., Mathew R.K., Polson E.S., Williams J., Wurdak H. (2018) SLAS Discovery 1:2472555218764623. doi: 10.1177/2472555218764623.

Chemically-induced neurite-like outgrowth reveals multicellular network function in patient-derived glioblastoma cells, da Silva B., Irving B.K., Polson E.S., Droop A., Griffiths H.B.S., Mathew R..K, Stead L.F., Marrison J., Williams C., Williams J., Short S.C., Scarcia M., O'Toole P.J., Allison S.J., Mavria G., Wurdak H. (2019) Journal of Cell Science 132(19). pii: jcs228452. doi: 10.1242/jcs.228452.

This project is part of the International PhD Academy: Medical Research

In line with the bespoke nature of our International PhD Academy a modified PhD project can be proposed dependent on students interests and background.

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject may also be required in some areas of the Faculty. For entry requirements for all other research degrees we offer, please contact us.

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The minimum requirements fpr this programme in IELTS and TOEFL tests are: • British Council IELTS - score of 7.0 overall, with no element less than 6.5 • TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.