Plasticity in cancer cells describes their inherent ability to undergo alterations and turn certain features on and off at different times. This flexibility sometimes occurs as a result of epigenetic alterations, chemical modifications in DNA that do not change the sequence, like what happens with mutations. Epigenetic changes can dictate how cells modify, or "package" DNA to make it fit into the nucleus of a cell. While the development of drugs to target specific mutational changes in DNA has efficacy in treating some types of cancer, targeting epigenetic modifications remains challenging because all modifications are reversible and turn on and off in response to environmental cues.
Phenotype switching, the phenomenon whereby cancer cells can move between different cellular states, includes phases of proliferation, the division and replication of cancer cells, and invasion, the movement of cancer cells into surrounding tissues. While scientists have long recognized that phenotype switching occurs in melanoma cells, the trigger promoting movement between states remains unclear.
A recent study published in Nature provides new insights into how melanoma cells undergo phenotype switching through remodeling of chromatin, complexes containing DNA, RNA, and proteins in the nucleus of cells. Previously thought to be triggered by chemical processes within the cell, this new study shows that the environment surrounding cancer cells regulates some epigenetic changes.
The researchers used a zebrafish model of melanoma to understand the mechanisms underlying phenotype switching. When melanoma cells experience pressure due to coming into close proximity with tightly packed surrounding tissues, cellular changes ensue. The study shows that when proliferating melanoma cells become confined within their environment, they stop dividing and activate pathways that promote migration and subsequent invasion into surrounding tissue.
The research identified a protein called HMGB2 as an integral player in pressure-driven phenotype switching in melanoma cells. When melanoma cells face mechanical stress induced by confinement, HMGB2 binds to chromatin, changing how the DNA is packaged into the nucleus. This change in DNA packaging exposes invasion-driving genes, and the study shows a clear correlation between HMGB2 levels and invasiveness. Further, cells expressing high levels of HMGB2, despite being less proliferative, become highly resistant to anti-cancer treatments.
The study's findings are not only novel but also informative for future drug development, as they demonstrate that mechanical stress can drive phenotype switching in melanoma cells. This discovery underscores a significant challenge in drug development, as many anti-cancer therapies target rapidly dividing cells, and the shift from a proliferative to invasive state can prevent some drugs from finding cancer cells. This new understanding of the role of mechanical stress in cancer cell behavior also opens up exciting possibilities for future research.
Sources: Cancer Res, Nature
