Dedifferentiation-Driven Oncogenic Stemness Promotes Tumor-Sustaining Adaptability in the Intestinal Epithelium

Intestinal tumors can arise either from mutations sustained in Lgr5? stem cells (bottom-up) or through dedifferentiation of lineage-committed epithelial cells (top-down). Using a Smad4 loss-of-function and ß-catenin gain-of-function mutant mouse model, we show that dedifferentiation-derived stem cells sustain tumorigenesis more effectively than mutant Lgr5? cells in the endogenous crypts. Bulk and single-cell RNA sequencing revealed transcriptional reprogramming and the emergence of oncogenic villus-derived stem-like cells. Complementary in vivo and organoid studies suggest that dedifferentiation-derived oncogenic stem cells possess superior tumor-initiating and sustaining capacity Overall design: Intestinal epithelial cells expressing red fluorescent protein, or the the stem cell marker CD44, was FACS isolated from wild type crypt, and the Smad4 loss-of-function and ß-catenin gain-of-function mutant crypt and villus epithelium and analyzed by single cell RNA-sequencing. Unlabeled cells from the wild type villus epithelium was also subjected to sc-RNA-sequencing.