Summary

Many tumors recapitulate the developmental and differentiation program of their tissue of origin, a basis for tumor cell heterogeneity. Although stem-cell-like tumor cells are well-studied, the roles of tumor cells undergoing differentiation in inducing the phenotypes associated with advanced cancers remains to be elucidated. Here, we employ Drosophila genetics to demonstrate that the native differentiation program of intestinal stem cells plays a key role in determining an intestinal tumor’s capacity to invade and induce various non-tumor-autonomous phenotypes. The differentiation program that generates absorptive cells enterocytes is aberrantly recapitulated in the intestinal tumors generated through activation of the Yap1 ortholog Yorkie. Elimination of tumor cells in the enterocyte lineage allows stem cell-like tumor cells to grow but suppresses invasiveness and reshapes various phenotypes associated with cachexia-like wasting by altering the expression of tumor-derived factors. Our study provides insight into how a native differentiation program determines a tumor’s capacity to induce the phenotypes associated with advanced cancers and suggests that manipulating the differentiation programs co-opted in tumors might be a way to treat some complications of cancer, including cachexia.