ZFP36L2 orchestrates stress-adaptive plasticity in intestinal regeneration and colorectal cancer metastasis

During intestinal wound healing and colorectal cancer (CRC) metastasis, differentiated cells can dynamically dedifferentiate into an intestinal stem cell (ISC) state to drive epithelial regeneration and metastatic outgrowth. Here we show that the RNA-binding protein ZFP36L2, which is mutated in 5-10% of CRC, is a critical stress-responsive orchestrator of dynamic dedifferentiation into an LGR5+ ISC state.

In mouse colon regeneration models, ZFP36L2 ablation inhibits dedifferentiation, ISC gene expression and function, and impairs intestinal regeneration. In human CRC, loss of ZFP36L2 function abrogates metastatic seeding and the outgrowth of LGR5+ canonical metastases, while promoting lineage plasticity and non-canonical differentiation into heterogeneous cell states. Mechanistically, we find that ZFP36L2 binds to stress-associated mRNAs containing AU-rich 3' UTRs, inducing the formation of dynamic biomolecular condensates associated with mRNA degradation and termination of the stress response.