Researchers from the Institute of Biomedical Engineering at the University of Toronto have identified a novel approach to potentially slow cancer progression by targeting a key enzyme that influences cancer-associated fibroblasts (CAFs). The enzyme, EHMT2 (G9a), plays a critical role in activating these fibroblasts, which are known to facilitate tumour cell invasion. By inhibiting EHMT2, the research demonstrated a reduction in both CAF abundance and their pro-invasive effects, offering a new avenue to explore cancer therapies that aim to reduce tumour aggressiveness.
This research was published in the recent issue of Biomaterials.
Cancer-associated fibroblasts are one of the most abundant cell types within the tumour microenvironment, contributing significantly to cancer progression. These cells help remodel the extracellular matrix and interact with tumour cells to promote cancer cell invasiveness, especially in regions where CAFs and tumour cells mix. Although previous efforts to reduce the influence of CAFs have shown limited success, this research aims to fill a gap in understanding by focusing on the epigenetic regulation of fibroblast activation. The GLAnCE (Gels for Live Analysis of Compartmentalized Environments) platform, developed in McGuigan’s lab was used to model the tumour environment and identify new therapeutic targets that could limit the pro-invasive nature of CAFs.
“Our findings suggest that targeting the epigenetic pathways involved in CAF activation, particularly the EHMT2 enzyme, can effectively reduce the ability of these fibroblasts to drive tumour cell invasion,” said Professor Alison McGuigan, the corresponding author of the study. “This approach could be an interesting strategy to complement existing cancer treatments, especially for cancers where CAF abundance is associated with poor prognosis.”
The study utilized the GLAnCE platform, a 3D in vitro culture system designed to mimic the tumour-CAF invasive margin. Researchers co-cultured head and neck squamous cell carcinoma (HNSCC) cells with patient-derived CAFs within this system, enabling the observation of cell interactions over time. The platform allowed for high-content imaging and analysis of the effects of various epigenetic inhibitors on CAF behaviour and tumour cell invasion. EHMT2 was found to significantly influence CAF hyperproliferation and promote a pro-invasive state, driving the formation of invasive tumour cell strands.
Looking forward, Professor McGuigan added, “We only followed up on one of the hits from our screen so in the future it will be exciting to explore other interesting hits from our screening data to identify combination targeting strategies to remodel the tumour microenvironment.”
The findings suggest that targeting CAF regulators like the EHMT2 enzyme could help reshape the tumour microenvironment to be less conducive to cancer spread, offering a potential new approach for cancer therapy development.