Verónica Rendo's research on targeting brain tumour evolution and treatment resistance
How functional genomics help us uncover the landscape of brain tumour vulnerabilities
Functional genomics is the study of how a specific gene contributes to a given biological process. Our understanding of gene function – particularly in the context of cancer– has increased tremendously in the last decade thanks to the development of CRISPR-based gene-editing technologies. In our group, we leverage these methods to study how gene alteration contributes to a specific phenotype, such as cancer cell growth or treatment response.
CRISPR technologies can be applied to study the effect of altering a particular gene at a time, or scaled up to study genome-wide perturbation effects in an unbiased, data-driven manner. Throughout our different projects, we leverage genome-scale pooled CRISPR screens to accelerate the discovery of clinically-relevant drug targets in neuro-oncology.
The effect of gene disruption or activation
An example is CRISPR knockout screens, where we use Cas9- or Cas12a-mediated gene editing to assess the effects of gene disruption on cancer cell viability, cell death phenotypes, and treatment response. Similarly, we conduct CRISPR activation screens where we use catalytically dead Cas9 (dCas9) fused to transcriptional activators to upregulate the expression of target genes. This enables the exploration of how gene overexpression impacts brain tumour growth and treatment response.
Overview of pooled CRISPR-based screens to uncover vulnerabilities driving treatment resistance in brain tumours.
BT145 glioblastoma patient-derived cells grown as neurospheres. Depletion of TP53 by CRISPR-Cas9 technology confers resistance to treatment with the p53 reactivator Navtemadlin.
Targeting Resistance to p53 Reactivation in High-Grade Glioma
Glioblastoma (GBM) and Diffuse Midline Glioma (DMG) are highly aggressive and universally fatal cancers of the brain, affecting both children and adults. The majority of high-grade gliomas carry a wild-type and functional version of the tumor suppressor gene TP53, making them susceptible to drugs that induce p53 signaling (i.e. p53 reactivators).
One of our focus areas is optimizing the use of p53 reactivating molecules in high-grade glioma (HGG) patients, for which our research has shown patient survival benefits (Rendo et al. Science Translational Medicine 2025). Although many TP53 wild-type HGGs initially respond to p53 reactivation strategies, resistance frequently emerges over time.
Treatment resistance due to altered transcription
Interestingly, we observe that in brain tumours, treatment resistance does not exclusively occur due to the acquisition of genetic mutations but is rather accompanied by adaptive changes in cellular transcriptional state.
Our research aims to characterize the transcriptional and epigenetic programmes that drive resistance to p53 reactivation in HGGs, with a particular focus on the role of differentiation-associated pathways. Using CRISPR-based tools, single-cell multi-omics, and lineage tracing, we are investigating how cell state dynamics influence treatment outcomes and identifying potential targets to overcome or prevent therapeutic resistance.
Assessment of transcriptional and epigenetic changes underlying cell cycle and apoptotic responses to p53 reactivators in different cellular contexts.
Characterizing chemo-persistent populations in embryonal brain tumours
Embryonal brain tumours are aggressive and heterogeneous cancers that primarily affect infants. Among them, atypical teratoid rhabdoid tumours (AT/RT) are the most common CNS tumour diagnosed in children under one year of age, with no defined standard treatment and poor prognosis.
Recurrence represents one of the major challenges for these patients – over 50 per cent relapse and, as of today, there are no standard treatments for recurrent AT/RT. Our research group is interested in identifying, characterizing and targeting the tumour cells that persist after therapy with clinically used regimens.
Some of our main research questions include:
- What is the phenotype of the population of treatment-persistent AT/RT cells?
- What are the mechanisms driving resistance in AT/RTs?
- Can we identify genetic dependencies and vulnerabilities?
To answer these questions, we use cellular barcoding methods and pooled CRISPR screens to track the genetic changes occurring in AT/RT cells over the course of treatment, and to identify drivers of resistance that can be translated into treatment options. We additionally apply multi-omics approaches (bulk RNA-seq, single-cell RNA-seq) to characterize these cancer cell populations.
Overview of our experimental workflow combining cellular barcoding and pooled CRISPR screens to characterize chemotherapy-persistent AT/RT cell populations. Created with Biorender.com.