This article introduces a developmental constraint model of cancer cell states and tumor heterogeneity, positing that cancer cells traverse a "developmental map" to generate diverse cell populations. It builds upon findings from single-cell transcriptomic analyses, which reveal that cancer cell states often recur across different tumor types, co-opt programs from normal physiological and developmental processes, and exhibit remarkable plasticity, allowing them to transition between states. The authors demonstrate how various cancer types, including melanoma, lung adenocarcinoma, glioblastoma, pancreatic ductal adenocarcinoma, rhabdomyosarcomas, and acute myeloid leukemia, show correspondence between cancer cell states and developmental hierarchies. This model suggests that the cell of origin plays a crucial role in determining the tumor's cellular composition and offers insights into how epigenetic mechanisms may encode and exploit these developmental constraints, providing potential avenues for therapeutic intervention by targeting cellular plasticity.
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