The role of innate cell differentiation in promoting yki3S/A intestinal tumor cell invasiveness and defining the systemic cachexia-like wasting phenotypes

Abstract

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 called 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. Meanwhile, enriching the intermediately differentiated tumor cells in the enterocyte lineage promotes a more robust and quicker tumor growth that lacks cell invasive properties but enhances tumor-derived factors expression, resulting in a more advanced manifestation of cachexia-like wasting syndrome in the host. This 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.