98 Oral - Stem Cells, Regeneration, and Tissue Repair
Friday April 08, 11:00 AM - 11:15 AM

Authors:
Inez Pranoto; Young Kwon

Affiliation: University of Washington, Seattle WA

Keywords:
p. other (Intestinal stem cell differentiation in cancer context); i. metastasis

The developmental program generates heterogeneous cell types that form and maintain tissue structure and physiology. Many tumors have been shown to recapitulate the developmental program of the tissue of origin, thus generating heterogenous cells within the tumors. Although tumor cells with stem cell-like properties have been extensively studied, how developmental programs recapitulated in tumors or tumor cells undergoing differentiation contribute to the adverse phenotypes associated with malignant tumors, such as metastasis and cachexia, are only poorly understood. We employed Drosophila midgut tumors driven by expression of the active form of yorkie (yki^3S/A) and revealed the striking heterogeneity of yki^3S/A midgut tumor cells, which aberrantly reconstituted the differentiation program to generate enterocytes (ECs)– polyploid absorptive intestinal epithelial cells. Blocking the EC differentiation program by expressing dominant negative Notch (N^DN) significantly reduced the heterogeneity of yki^3S/A tumor cells by eliminating the differentiating yki^3S/A tumor cells, leading to formation of fully grown tumors comprising only intestinal stem cell-like yki^3S/A tumor cells. Of note, blocking the EC differentiation program was sufficient to eliminate a population of yki^3S/A tumor cells that can invade and migrate to disseminate from the midguts. Interestingly, eliminating yki^3S/A tumor cells undergoing EC differentiation significantly altered the expression of multiple tumor-driven secreted factors and the tumor’s propensity for inducing the tumor non-autonomous and systemic phenotypes. In particular, blocking the EC differentiation program significantly decreased the expression of wasting factors in tumors and suppressed multiple wasting phenotypes, including ovary atrophy, fat body degeneration, and ‘bloating syndrome’. Our study demonstrates that the EC differentiation program recapitulated in yki^3S/A midgut tumors is crucial for the tumor cells’ capacity to disseminate from the midguts and induce certain wasting phenotypes. This work provides insights into how the contextual information in the tissue of origin can give rise to tumor’s ability to induce the phenotypes associated with malignant tumors. Thus, we propose that manipulating the developmental/differentiation programs recapitulated in tumors is a way to modulate tumor behavior for the treatment of the complications associated with the advanced cancers.