Differential YAP expression in glioma cells induces cell competition and promotes tumorigenesis

Intratumor heterogeneity associates with cancer progression and may account for a substantial portion of therapeutic resistance. Although extensive studies have focused on the origin of the heterogeneity, biological interactions between heterogeneous malignant cells within a tumor are largely unexplored. Glioblastoma (GBM) is the most aggressive primary brain tumor. Here, we found that the expression of Yes-associated protein (YAP) is intratumorally heterogeneous in GBM. In a xenograft mouse model, differential YAP expression in glioma cells promotes tumorigenesis and leads to clonal dominance by cells expressing more YAP. Such clonal dominance also occurs in vitro when cells reach confluence in the two-dimensional culture condition or grow into tumor spheroids. During this process, growth of the dominant cell population is enhanced. In tumor spheroid, such enhanced growth is accompanied by increased apoptosis in cells expressing less YAP. The cellular interaction during clonal dominance appears to be reminiscent of cell competition. RNA-seq analysis suggested that the interaction induces expression of tumorigenic genes, which may contribute to the enhanced tumor growth. These results suggested that tumorigenesis benefits from competitive interactions between heterogeneous tumor cells. Examination of gene expression in cell lines growing in different tumor spheroids containing two different groups of cells. 8 samples are analyzed without duplicates.