Cancer cells undergo a cascade of increasingly adaptive cellular states as they undergo drug adaptation, according to research from the lab of Itai Yanai, PhD, at the NYU Grossman School of Medicine. This “resistance continuum” starts with initial sensitivity and ends with stable resistance, bookending a series of state transitions that include the physiological adaptation and dedifferentiation axes.
This research, published in Nature, reveals a connection between lineage plasticity and partial endothelial to mesenchymal transition (EMT), which has been linked to resistance. While EMT induction directly contributes to partial resistance, the researchers contend that, in the long run, it more broadly promotes phenotypic plasticity, which opens the door for the emergence of new mechanisms that heighten drug resistance. The study advocates for complementary therapies that target the mechanisms underlying adaptive cell-state transitions.
Malignant moving targets
An inherent obstacle in cancer treatment is the persistent capacity of malignant cells to acquire resistance to previously efficacious therapies progressively. The selection of genetic mutations that allow cells to evade therapy has long been the basis of models used to explain the emergence of resistance.
Recent years, however, have shown the importance of non-genetic mechanisms. In particular, some cancer cells can become drug-tolerant persister cell states through transcriptional reprogramming, evading therapeutic elimination. It is possible for heritable adaptive states to eventually lead to stable resistance, even if a drug-tolerant state can be undone after long-term exposure.
“Resistence continuum”
First author Gustavo S. França, PhD, and his colleagues did a series of longitudinal experiments to look into and functionally characterize these trajectories to learn more about the unknown underlying dynamics and phenotypic trajectories that control drug adaptation. They demonstrate that resistance develops on a spectrum due to cell-state changes and a gradual increase in cell fitness. The cellular adaptation process, known as the ‘resistance continuum,’ involves gradually forming gene expression programs and strengthening cell states through epigenetic mechanisms. The ability of cells to alter their phenotype and rewire their metabolism in response to stress supports this adaptation. These findings back up the idea that stemness programs or the epithelial-to-mesenchymal transition, which is another name for phenotypic plasticity, do not completely stop change but rather allow it.
According to the authors, their findings suggest that gradual exposure to injury can improve a cell population’s fitness by allowing cells to “learn” and fine-tune stress regulatory networks, priming stable adaptive states. Initially, drug-sensitive cells accumulate transcriptional and epigenetic changes in response to stress, resulting in more robust responses when stimulated again. They speculate that a similar process might occur during patient treatment, depending on drug gradients and tumor spatial heterogeneity. Early in the resistance continuum, drug-tolerant persister cells may be drug-tolerant and depend on stress-related programs and chromatin remodeling.
Through systematic genetic perturbations, the researchers identify the acquisition of metabolic dependencies, exposing vulnerabilities that can be exploited therapeutically. The “resistance continuum” highlights the need for additional therapies that target the processes that allow cells to change their state during adaptation.
