Evolutionary insights into tumor progression: integrating genetic mutations and phenotypic plasticity

Cancer progression is an evolutionary process shaped by clonal dynamics within a complex tumor ecosystem. Deciphering tumor evolution solely as the gradual accumulation of mutations that confer selective advantages and promote the expansion of selected cellular clones does not fully capture the complexity and dynamics of cancer development. Emerging evidence increasingly underscores the critical contribution of non-genetic regulatory mechanisms in shaping cellular behavior, revealing a remarkable degree of cellular plasticity that enables cells to dynamically adapt their phenotype and functional state in response to intrinsic and extrinsic cues. In this review, we discuss how tumor evolution is propelled not only by stable genetic mutations, which initiate malignant transformation and confer proliferative advantages, but also by dynamic adaptive programs. These mechanisms, including the epithelial–mesenchymal transition, cellular dormancy and metabolic reprogramming, enable tumor cells to survive microenvironmental stress and facilitate metastatic dissemination. Herein, we conceptualize tumor progression as the evolutionary selection of highly adaptable clonal populations, governed by a synergistic interplay between genetic fitness and cellular plasticity. We propose that understanding the convergence of stable genetic alterations and reversible epigenetic states is critical for developing novel therapeutic strategies to effectively target metastatic disease.