Research Overview

Co-mutations, Heterogeneity and Drug Resistance

Why tumours sharing the same actionable driver respond so differently to the same drug.

FGFR2 fusions occur in 10–20% of intrahepatic cholangiocarcinoma, yet only 20–35% of patients respond to approved FGFR inhibitors. In a murine model, we showed that co-occurring KRAS mutations drive primary resistance, while MEK co-targeting restores sensitivity (Kendre et al., Hepatology, 2021). This established that treatment response depends not only on the driver, but also on its genetic context.

We then mapped co-mutation patterns across actionable drivers in human intrahepatic cholangiocarcinoma, revealing how genetic context shapes therapeutic vulnerabilities (Kendre et al., Journal of Hepatology, 2023). We are now investigating candidate co-mutations that may drive resistance and identify opportunities for combination therapy.

The same principle extends beyond cholangiocarcinoma: in colorectal cancer, RNF43 alterations associate with BRAF V600E and MSI-high status (Vogel et al., JCO Precision Oncology, 2024). A driver does not act in isolation — the mutations that accompany it can change what it means for treatment.

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Host Genetics of Liver Fibrosis

How a person's own genetic make-up shapes whether, and how fast, an injured liver scars.

Two people with the same liver injury can follow very different courses — one progressing to advanced fibrosis, the other barely at all. We investigate the host genetic determinants behind that variability: which inherited factors accelerate or restrain fibrotic progression, and whether any of them are tractable points of intervention.

One strand follows the strong and still poorly explained male bias in chronic liver disease, asking how Y chromosome-linked genes contribute to fibrosis. Another characterises the host determinants of HCV-driven fibrosis. Both are areas where careful mechanistic work could explain a well-documented clinical pattern that remains largely unaccounted for.

Host–Microbe Communication and Synthetic Biology

Inter-kingdom signalling in the tumour microenvironment, and genetic circuits built to probe it.

Bacteria coordinate their behaviour through quorum sensing. We study how AHL-mediated signals act on host cells and what that means for immune regulation and oral squamous cell carcinoma, and we build bacterial–host genetic circuits as programmable tools for probing that communication.