Disruptions in cell fate decisions and transformed enteroendocrine cells drive intestinal tumorigenesis in Drosophila.

Most epithelial tissues are maintained by stem cells that produce the different cell lineages required for proper tissue function. Constant communication between different cell types ensures precise regulation of stem cell behavior and cell fate decisions. These cell-cell interactions are often disrupted during tumorigenesis, but mechanisms by which they are co-opted to support tumor growth in different genetic contexts are poorly understood. Here, we introduce PromoterSwitch, a genetic platform we established to generate large, transformed clones derived from individual adult Drosophila intestinal stem/progenitor cells. We show that cancer-driving genetic alterations representing common colon tumor genome landscapes disrupt cell fate decisions within transformed tissue and result in the emergence of abnormal cell fates. We also show that transformed enteroendocrine cells, a differentiated, hormone-secreting cell lineage, support tumor growth by regulating intestinal stem cell proliferation through multiple genotype-dependent mechanisms, which represent potential vulnerabilities that could be exploited for therapy. [Display omitted] • PromoterSwitch (PS) allows more refined genetic manipulations in Drosophila • Cancer-driving genetic alterations disrupt cell fate decisions in the intestine • Transformed enteroendocrine cells (EEs) promote intestinal transformation • The EE hormone Tachykinin supports tumorigenesis through genotype-dependent mechanisms Quintero and Bangi use a genetic tool to show that cancer-driving genetic alterations disrupt cell fate decisions in the adult fly intestine, resulting in tumor-like growths that capture the cell-type heterogeneity of cancer. They also identify a tumor-promoting role for hormone-secreting enteroendocrine cells mediated by multiple genotype-dependent mechanisms. [ABSTRACT FROM AUTHOR]