Condensates and cell states: A new paradigm for understanding tumor biology

Traditionally, cells have been classified by their type. Identifying cell types was deemed vital for understanding their biological processes. More recently, cell-type classification has been recognized as insufficient. Cells have many transient states that depend on their spatial environment. Thus, the current cell-state description recognizes that a cell is dynamic, varying over developmental time, location, senescence, and disease. In addition, while cell states refer to the functional behavior of the cells, biomacromolecular condensates are now recognized as the membraneless structures within them, which, by concentrating functionally related proteins, make the function happen. Here, we 1) clarify the molecular basis of the current separation between cell types and states and point to the merit of the "cell states", which make the classical "cell type" distinction expendable; 2) discuss how fundamental physical principles evolved the functionally-specific, conformationally-biased biomacromolecular condensates; and 3) consider the pharmacology of cell states and condensates. Recent reports highlighted condensates as drug targets. While important, drugs designed to dismantle condensates may lack the specificity of therapies targeting cell-states-defining epigenetic regulators. Fourth and most importantly, 4) we consider the transition of primary cancer cells, linking cell states and condensates to tumor proliferation. We propose that the migration of cancer cells to distant tissues is primarily influenced by cell states and sustained by their multi-condensate organization. Furthermore, the high genetic homogeneity of untreated cancers-across both primary tumors and metastases-underscores the critical role of the transient nature of cell states.