Tissue-location specific transcription programs drive tumor initiation dependencies in colon cancer

Abstract

Abstract It is unknown why cancers of the same tissue-type but in anatomically distinct locations exhibit different molecular dependencies for tumorigenesis. Proximal and distal colon cancers (CC) exemplify such characteristics, with BRAFV600E predominantly occurring in proximal CC along with increased DNA methylation phenotype. Using mouse colon organoids, we show that proximal and distal colon stem cells have distinct transcriptional programs regulating stemness and differentiation. The homeobox transcription factor, Cdx2, frequently silenced by DNA methylation in proximal colon cancers, was identified as a key mediator of the differential transcriptional programs. Cdx2-mediated proximal colon-specific transcriptional program is concurrently tumor suppressive, and its loss is critical for BRAFV600E-driven transformation of proximal colon stem cells. Human proximal CC with CDX2-downregulation showed similar transcriptional program as the mouse proximal organoids with Cdx2 loss. Our results suggest a model in which developmental transcription factors maintain tissue-location specific transcriptional programs that create tissue-type origin specific dependencies for tumor initiation.