Our Research
Most cancers are characterised by cellular and molecular heterogeneity. This heterogeneity can contribute to therapy resistance, as cellular subpopulations may evade treatment through diverse mechanisms, leading to recurrence. Our research focuses on understanding the contribution of intratumoral heterogeneity to therapy resistance. We employ a range of approaches, including mass cytometry, single-cell transcriptomics, functional genomics, patient-derived models, and computational analyses, to dissect the cellular and molecular diversity and identify vulnerabilities that can be therapeutically exploited.
Current projects in the lab aim to characterise resistant tumour subpopulations, investigate adaptive resistance mechanisms, and explore strategies to overcome treatment failure. We are focused on glioblastoma (GBM), the most aggressive primary brain tumour, which exemplifies these challenges. Standard therapies, including surgery, radiation, and chemotherapy, provide only temporary control, highlighting the urgent need to develop more effective, tailored treatment strategies. By uncovering the key drivers of resistance, our ultimate goal is to develop new therapeutic approaches that improve outcomes for patients.
GBM Cellular Plasticity
Some cells can switch from one type to another—and even switch back. For example, certain epithelial cells can transition into mesenchymal cells during wound healing, then revert once the tissue is repaired. This ability, known as cell plasticity, helps maintain stability in changing environments, such as during tissue repair after injury.
In brain cancer, particularly gliomas, plasticity allows tumour cells to adopt different identities in response to environmental cues or therapy. When exposed to ionising radiation or chemotherapy, some glioma cells shift into alternative cell states, such as slow-cycling mesenchymal-like phenotypes, that are believed to be more resistant to treatment. After therapy, these resilient cells may revert to more proliferative states, fuelling tumour regrowth and progression.
Despite its central role in treatment resistance and recurrence, the molecular mechanisms driving cancer cell plasticity in the brain remain poorly understood. Targeting the programs that enable such identity shifts could offer a powerful strategy to prevent relapse and eliminate therapy-resistant populations in brain tumours.
Cell state resistance mechanisms
As cancerous cells transition between different cellular states, they acquire distinct molecular features that can influence how they respond to therapy. These states are not random but follow defined transcriptional and epigenetic programs, each associated with specific vulnerabilities and mechanisms of resistance. For example, glioma cells in a stem-like state may upregulate DNA repair pathways or anti-apoptotic signals, conferring resistance to radiation and temozolomide.
Understanding the functional properties of these states offers a powerful opportunity to identify therapeutic weak points. Targeting the unique dependencies of specific cell states could sensitise tumours to existing treatments or reveal new combination strategies. Crucially, these vulnerabilities may only be apparent in the context of a given cell state, highlighting the need to map the dynamic state landscape of tumours over time and during therapy.
We are beginning to uncover these state-specific resistance programs in brain cancer. Such insights could pave the way for adaptive, state-targeted therapies that anticipate tumour changes and improve long-term treatment outcomes.