Joint experimental/theoretic approaches for understanding the cell state transition and epigenetic plasticity associated with adaptive resistance in cancer cells
Epigenetic plasticity is increasingly appreciated to be as significant as genetic mutations in driving therapy resistance and disease progression in a variety of cancer types for a broad range of therapeutic regimes. Epigenetic plastic cancer cells can hijack developmental programs to gain drug resistance by reversibly dedifferentiating towards stem-like states. The transient cell state switching enables cancer cells to survive drug treatment prior to the emergence of genetically resistant derivatives. This resistance mechanism, termed adaptive resistance, represents a fundamental departure from the textbook paradigm in which therapy resistance arises from the Darwinian-type selection of cancer cells that carry resistance-leading mutations. In the meantime, drug-tolerant cancer cells can also transiently increase their genetic instability and mutability (termed adaptive mutability) to facilitate the acquisition of resistance-leading mutations. The transiently heritable resistant phenotype and its reversible nature implicate a dynamic process underpinned by remodeling of the epigenetic landscape.
Using theoretic and computational approaches coupled with multi-omics and single-cell analyses, we interrogate the molecular mechanism responsible for the initiation and coordination of adaptive cell state changes and adaptive mutagenesis and resolve how tumor heterogeneity and dynamic evolution contribute to these processes.
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