Cellular plasticity of cancer: roles of biomolecular condensates and ecDNA

Cancer is characterized not only by malignant transformation driven by genomic alterations but also by remarkable cellular plasticity that enables adaptation to environmental and therapeutic stress. Cancer cell plasticity frequently involves extensive remodeling of gene regulatory and transcriptional networks arising from complex interactions between genetic alterations and nongenetic regulatory mechanisms. The regulatory sources of cancer cell plasticity include changes in RNA molecules, such as microRNAs, alterations in RNA processing, epigenetic reprogramming, and higher-order cellular organization. In particular, biomolecular condensates-membraneless organelles formed through phase separation-and extrachromosomal DNA (ecDNA) have gained attention as important regulators of gene expression and cellular heterogeneity in cancer. Alterations in biomolecular condensates in cancer cells are frequently associated with dysregulated gene regulation and cell signaling. In addition, ecDNA represents an emerging mechanism that mediates high-level oncogene transcription, tumor heterogeneity, and drug resistance in cancer. This review summarizes recent advances in understanding how biomolecular condensates and ecDNA contribute to the regulation of cancer cell plasticity and discusses their implications for tumor evolution and therapeutic resistance. We also outline the usefulness of several CRISPR-based methods to test the roles of ecDNA, including generation of ecDNA-like circular DNA as model systems, optimization of Cas9 activity for prevention of Cas9-induced ecDNA loss and efficient ecDNA knock-in, and CRISPR interference-based perturbations.