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

Phenotypic plasticity is a hallmark of cancer, yet the molecular switches required for cell fate reprogramming are poorly understood. 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. Together, this work defines ZFP36L2 acts as a critical molecular switch coupling stress sensing with phenotypic plasticity, driving cellular dedifferentiation essential for re-establishing the ISC state during wound healing and metastasis. In ZFP36L2 deficient CRC, inability to re-enter the LGR5+ state during metastatic outgrowth drives non-canonical lineage plasticity, associated with poor clinical outcomes. This SuperSeries is composed of the SubSeries listed below.