Frank, S. A. 2025. How cancer arises: genetics releases, plasticity creates, genetics stabilizes. Proceedings of the National Academy of Sciences USA 122:e2505377122

Cancer is the origin of a novel tissue that attracts resources, spreads beyond boundaries, avoids normal controls, and escapes immunity. How does a novel tissue arise? The puzzle is that two seemingly different processes appear to be the primary driving force. On the one hand, overwhelming evidence links (epi)genetic driver mutations to the origin and progression of tumors. Common oncogenic mutations such as KRAS accelerate cell division, and common knockouts of tumor suppressors such as TP53 abrogate cell death or checks on cell division. On the other hand, cancerous tissues create complex traits that require intricate changes in cells and multiple interactions between different cell types. Such novelty often arises by hijacking the developmental plasticity that normally creates the diverse cells and tissues of our bodies from a single original zygotic cell. How can we reconcile the simple genetic changes in carcinogenesis with the complex developmental plasticity that creates novel tissues? This perspective advocates a new model. (Epi)genetic mutations release developmental plasticity. That developmental plasticity creates novel cellular interactions and complex tissues. Initially, novel traits created by developmental plasticity may not be stably heritable, thus subsequent (epi)genetic changes must stabilize the phenotypic novelty. Recent studies show how classic oncogenic and tumor suppressor driver mutations, such as KRAS and TP53, may primarily act in early carcinogenesis as broad releasers of developmental plasticity rather than as stimulators of cell division or knockout of limitations on cellular clonal expansion. In the new model, genetics releases, plasticity creates, and genetics stabilizes.