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While 20–30% of colorectal cancers (CRCs) may arise from precursors with serrated glands, only 8–10% of CRCs manifest serrated morphology at diagnosis. Markers for distinguishing CRCs arising from ‘serrated’ versus ‘conventional adenoma’ precursors are lacking. We studied 36 human serrated CRCs and found CDX2 loss or  BRAF  mutations in ~60% of cases and often together (p = 0.04). CDX2 Null /BRAF V600E  expression in adult mouse intestinal epithelium led to serrated morphology tumors (including carcinomas) and BRAF V600E  potently interacted with CDX2 silencing to alter gene expression. Like human serrated lesions, CDX2 Null /BRAF V600E -mutant epithelium expressed gastric markers. Organoids from CDX2 Null /BRAF V600E –mutant colon epithelium showed serrated features, and partially recapitulated the gene expression pattern in mouse colon tissues. We present a novel mouse tumor model based on signature defects seen in many human serrated CRCs – CDX2 loss and BRAF V600E . The mouse intestinal tumors show significant phenotypic similarities to human serrated CRCs and inform about serrated CRC pathogenesis.

BRAF V600E cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis