Cancer cells are notoriously flexible, taking on new features as they move around the body. Many of these changes are due to epigenetic modifications, which influence how DNA is packaged, and not due to mutations in the DNA itself. Such modifications are difficult to target for cancer therapy because they are reversible and can flip on and off.
Epigenetic changes have traditionally been thought to arise from internal cellular processes that result in the chemical tagging of DNA and its histone protein packaging—such as histone methylation or DNA acetylation. But now, a new study led by Ludwig Oxford’s Richard White and Miranda Hunter of the Memorial Sloan Kettering Cancer Center shows that the physical environment in which these cells land is also a key instigator of epigenetic transformation.
Using a zebrafish model of melanoma, White, Hunter and their colleagues show that when tumour cells are tightly confined by surrounding tissues, they undergo structural and functional changes. Rather than continuing to divide rapidly, the cells activate a program of ‘neuronal invasion’, enabling them to migrate and spread into the surrounding tissue.
At the centre of this transformation is HMGB2, a DNA-bending protein. The study demonstrates that HMGB2 responds to the mechanical stress of confinement by binding to chromatin, altering how genetic material is packaged. This exposes regions of the genome linked to invasiveness, making them newly available for gene expression. As a result, cells with high levels of HMGB2 become less proliferative but more invasive and resistant to treatment.
Read the full story on the Nuffield Department of Medicine website.