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

Abstract

SUMMARYMost epithelial tissues are maintained by stem cells that produce the different cell lineages required for proper tissue function. Constant communication between different cell types that make up a tissue is essential to ensure that all cell lineages are produced at appropriate numbers and to mount regenerative responses to injury, infection, and other environmental stresses. Cancer-driving alterations change the intrinsic properties of transformed cells and disrupt stem cell regulation, cell fate decisions, and cell-cell communication within transformed tissue. However, mechanisms by which these processes are disrupted and co-opted to support tumorigenesis are not well understood. Here, we report a novel genetic platform, PromoterSwitch, that allows targeting of genetic manipulations to a small subset of cells of any tissue or cell type of interest and all their subsequent progeny. We use this technology to generate large, transformed clones derived from individual stem/progenitor cells in the adult Drosophila intestine. We show that cancer-driving genetic alterations representing common colon tumor genome landscapes drive disruptions in cell fate decisions within transformed clones and changes in the relative abundance of different intestinal cell lineages. We also uncover a critical, context-dependent role for the differentiated, hormone-producing enteroendocrine (EE) cells in the growth and maintenance of transformed clones. Our analysis in different genetic contexts provides insights into how the intrinsic properties of transformed cells —dictated by the genetic alterations they carry— determine their response to their environment and dependence on niche signals. A better mechanistic understanding of disruptions of cell-cell communication, stem cell regulation, and cell fate decisions within tumors could reveal novel vulnerabilities and druggable regulatory nodes that can be exploited for therapy. Understanding how tissues respond to the emergence of cells with cancer-driving genetic alterations also provides insights into stem cell biology and epithelial homeostasis.