Nature | 蒋清雯等揭示ZFP36L2是调控肠道再生与结直肠癌转移可塑性的分子开关
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TL;DR — A Nature paper (Aug 5, 2026) from Karuna Ganesh's lab at MSKCC, first-authored by Qingwen Jiang, identifies ZFP36L2 as the molecular switch that terminates stress signaling to let intestinal cells de-differentiate into LGR5+ stem cells, driving both gut regeneration and classical colorectal cancer metastasis. It matters because it converts "tumor plasticity" from a descriptive phenomenon into a defined, druggable regulatory circuit — with a cautionary twist for targeting it.
- Mechanism: stress (injury, metastatic niche) activates AP-1 (FOS/FOSB/ATF3) and upregulates ZFP36L2, which binds AU-rich elements in 3'UTRs of hypoxia/inflammation/apoptosis transcripts and accelerates their decay; AlphaFold-predicted intrinsically disordered N/C termini enable liquid–liquid phase separation into cytoplasmic condensates that sequester and degrade the stress mRNAs.
- Loss of function blocks regeneration in DSS colitis and Lgr5-DTR stem-cell-ablation mice plus organoids, and sharply reduces liver micrometastasis in splenic-injection PDO xenografts.
- Clinically paradoxical: surviving ZFP36L2-null metastases shift lineage — LGR5 down, squamous CK5 and neuroendocrine CHGB up — matching FFPE patient samples with ZFP36L2 loss-of-function mutations and worse prognosis, so simple inhibition may select for more malignant states.
- Methods span 25-patient matched single-cell transcriptomics (normal/primary/metastasis), HyperTRIBE RNA-interaction sequencing, Actinomycin D and SLAM-seq decay assays, and live-cell condensate imaging; recurrent ZFP36L2 loss in pancreatic, urothelial and melanoma cohorts (plus ZFP36L1/ZFP36 in SCLC/AML) suggests a conserved cross-cancer axis detectable by MSK-IMPACT.
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Nature | 蒋清雯等揭示ZFP36L2是调控肠道再生与结直肠癌转移可塑性的分子开关
TL;DR — A Nature paper (Aug 5, 2026) from Karuna Ganesh's lab at MSKCC, first-authored by Qingwen Jiang, identifies ZFP36L2 as the molecular switch that terminates stress signaling to let intestinal cells de-differentiate into LGR5+ stem cells, driving both gut regeneration and classical colorectal cancer metastasis. It matters because it converts "tumor plasticity" from a descriptive phenomenon into a defined, druggable regulatory circuit — with a cautionary twist for targeting it.
- Mechanism: stress (injury, metastatic niche) activates AP-1 (FOS/FOSB/ATF3) and upregulates ZFP36L2, which binds AU-rich elements in 3'UTRs of hypoxia/inflammation/apoptosis transcripts and accelerates their decay; AlphaFold-predicted intrinsically disordered N/C termini enable liquid–liquid phase separation into cytoplasmic condensates that sequester and degrade the stress mRNAs.
- Loss of function blocks regeneration in DSS colitis and Lgr5-DTR stem-cell-ablation mice plus organoids, and sharply reduces liver micrometastasis in splenic-injection PDO xenografts.
- Clinically paradoxical: surviving ZFP36L2-null metastases shift lineage — LGR5 down, squamous CK5 and neuroendocrine CHGB up — matching FFPE patient samples with ZFP36L2 loss-of-function mutations and worse prognosis, so simple inhibition may select for more malignant states.
- Methods span 25-patient matched single-cell transcriptomics (normal/primary/metastasis), HyperTRIBE RNA-interaction sequencing, Actinomycin D and SLAM-seq decay assays, and live-cell condensate imaging; recurrent ZFP36L2 loss in pancreatic, urothelial and melanoma cohorts (plus ZFP36L1/ZFP36 in SCLC/AML) suggests a conserved cross-cancer axis detectable by MSK-IMPACT.