Dissecting the role of the choroid plexus in gliomagenesis

Primary supervisor: Simona Parrinello, UCL

Secondary supervisor: Ilaria Malanchi, Francis Crick Institute; Laura Pellegrini, King’s College London

Project

Glioblastoma (GB) is an incurable and devastating disease with a median survival at less than 15 months, a prognosis that has not improved for several decades. There is therefore a pressing medical need for the development of more effective, conceptually different approaches.

Most of our knowledge of GB biology derives from studying advanced tumours, characterised by pervasive therapy resistance and an immune suppressive microenvironment. In contrast, despite the implications for future interception strategies, the earlier, more tractable stages of gliomagenesis remain poorly understood. We have recently uncovered a critical role for injury programmes in driving GB initiation and early progression (Clements et al., Nature 2025).  Specifically, we found that as early tumour cells begin to expand within the brain, they physically injure surrounding axons, triggering a wound healing response that creates a permissive microenvironment for GB formation.

Exciting preliminary data suggest that the choroid plexus (ChP) is a critical component of this injury-induced pro-tumourigenic niche. The choroid plexus is a specialized structure within the brain’s ventricles that produces cerebrospinal fluid (CSF), maintains the blood–CSF barrier, secretes biologically-active molecules that regulate brain homeostasis and regulates the trafficking of immune cells to the brain. In disease, the ChP undergoes structural and functional remodelling that actively contribute to a variety of neuroinflammatory and neurodegenerative disorders, but its role in GB is largely unknown.

This project will mechanistically dissect the role of the ChP in gliomagenesis across three main aims.

1. Characterise the cellular composition and secretome of the ChP in gliomagenesis. The Parrinello lab has developed disease-relevant mouse models that allow the analysis of tumour cells and their microenvironment from acquisition of mutations to terminal disease stages. Using these models, the student will carry out time-course analyses of ChP structure and CSF composition by combining multiplex immunofluorescence and mass spectrometry.
2. Functionally test ChP-tumour interactions. We will dissect ChP-tumour crosstalk in two complementary model systems: 1. Acute organotypic slices from mouse tumours co-cultured with ChP explants or exposed to ChP-conditioned media. 2. Human CSF-producing ChP organoids, a state-of-the-art model established by the Pellegrini lab (Pellegrini et al., Science 2020), co-cultured with patient-derived GB cells. These systems will be combined to examine effects of ChP on tumour cell proliferation and the reciprocal responses of the ChP to tumour cells. Gain- and loss-of-function experiments targeting candidate mediators from Aim 1 will establish causality and determine their functional contribution.
3. Assess the role of the ChP in gliomagenesis. In collaboration with senior postdocs, the student will determine the impact of ChP secreted factors on early progression using genetic and pharmacological approaches in the mouse models

This work will provide fundamental insights into GB and ChP biology and has the potential to identify biomarkers and targetable mediators of disease progression.

Candidate background

The project would suit a highly motivated, curiosity-driven student with a background in neurogenesis, neuroscience or developmental neurobiology.

Potential placements

1. Laura Pellegrini, Centre for Developmental Neurobiology, King’s College London
2. Ciaran Hill, Cancer Institute, UCL
3. Ilaria Malanchi, Francis Crick Institute

References

1. M. Clements et al. Axonal Injury is a targetable driver of glioblastoma progression. Nature 2025
2. L. Pellegrini et al. Human CNS barrier-forming organoids with cerebrospinal fluid production. Science 2020
3. M. Clements et al. Generation of immunocompetent somatic glioblastoma mouse models through in situ transformation of subventricular zone neural stem cells. STAR protocols. 2024
4. Amodeo et al. Diet suppresses glioblastoma initiation in mice by maintaining quiescence of mutation-bearing neural stem cells. Dev Cell 2023
5. Garcia Diaz et al. Glioblastoma cell fate is differentially regulated by the microenvironments of the tumor bulk and infiltrative margin. Cell Reports 2023.