mediates enhancement of intestinal tumorigenesis caused by inactivation of .

The CSF1 receptor (CSF1R) encoding mRNA represents a direct target of miR-34a. However, the relevance of the suppression of by miR-34a for intestinal tumor suppression mediated by the p53/miR-34a pathway has remained unknown. Here, mice with intestinal-epithelial cell (IEC)-specific deletions of showed increased formation of adenomas and decreased survival, whereas deletion of decreased adenoma formation and increased survival. In adenomas deletion of enhanced proliferation, STAT3 signaling, infiltration with fibroblasts, immune cells and microbes, and tumor stem cell abundance and decreased apoptosis. Deletion of had the opposite effects. In addition, homeostasis of intestinal secretory and stem cells, and tumoroid formation were affected in opposite directions by deletion of and . Concomitant deletion of and neutralized the effects of the single deletions. mRNAs containing Mir34a seed-matching sites, which encode proteins related to EMT (epithelial-mesenchymal transition), stemness and Wnt signaling, were enriched after inactivation in adenomas and derived tumoroids. and were characterized as direct targets of Mir34a and Csf1r signaling. -inactivation related expression signatures were associated with CMS4/CRISB+D, stage 4 CRCs and poor patient survival. In tumoroids the loss of conferred resistance to 5-FU which was mediated by . This study provides genetic evidence for a requirement of Mir34a-mediated suppression for intestinal stem/secretory cell homeostasis and tumor suppression, and suggests that therapeutic targeting of CSF1R may be effective for the treatment of CRCs with defects in the p53/miR-34a pathway.