Targeting the epigenome and the integrated stress response to normalize colorectal cancer subclonal plasticity and progression

Epigenetic mechanisms are implicated in enabling the acquisition of new phenotypic traits as drivers of colorectal cancer progression, rather than new genetic mutations or expansion of existing mutant clones. It remains unclear, however, which epigenetic mechanisms sustain colorectal cancer plasticity, how they are induced, and how this plasticity generates subclonal diversity that drives the aggressive cancer phenotype.

Here we identify the integrated stress response as an inducer of colorectal cancer cell plasticity, subclonal diversity, and tumor progression in the stress-surviving cells. Combined analysis of chromatin accessibility and gene transcription profiling in these cells found the emergence of an endogenous interferon response as a key phenotypic trait associated with subclonal colorectal cancer cell diversity, treatment resistance and heightened aggressiveness.