KRAS-ERK Signaling Drives Metastasis in Colorectal Cancer via Phosphorylation Dependent Activation of the ZBTB20-TGFBR2 Axis

We integrated data from clinical databases (TCGA, CPTAC) with experimental validation using human CRC cell lines, a tissue microarray, and two distinct in vivo metastasis models (liver and lung colonization). ZBTB20 expression and function were analyzed by IHC, Western blotting, Transwell assays, and RNA-seq integrated with ChIP-seq data. The mechanism of ZBTB20 regulation was investigated via co immunoprecipitation, mass spectrometry, truncation analysis, site-directed mutagenesis, and luciferase reporter assays. Statistical significance was determined using Student's t tests, ANOVA, and survival analysis. Our findings delineate a novel KRAS-ERK-ZBTB20-TGFBR2 signaling axis that is a critical driver of metastasis in KRAS-mutant CRC. The robust efficacy of a TGFBR2 degrader in multiple in vivo models validates this axis as a viable therapeutic target, offering a promising strategy to inhibit metastatic progression in patients with this aggressive disease. Overall design: RNA-seq profiling of wildtype SW620 cells and their knockdown derivatives (shZBTB20).