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. Overall design: Examination of gene expression in cell lines growing in different tumor spheroids containing two different groups of cells. 8 samples are analyzed without duplicates.

肿瘤内异质性（Intratumor heterogeneity）与癌症进展密切相关，且可能是治疗耐药性产生的重要诱因。尽管已有大量研究聚焦于该异质性的起源，但肿瘤内异质性恶性细胞之间的生物学相互作用仍未得到充分探索。胶质母细胞瘤（Glioblastoma, GBM）是恶性程度最高的原发性脑肿瘤。本研究发现，Yes相关蛋白（Yes-associated protein, YAP）在GBM中呈现肿瘤内异质性表达。在异种移植小鼠模型（xenograft mouse model）中，胶质瘤细胞内YAP的表达差异可促进肿瘤发生，并使高表达YAP的细胞获得克隆优势。该克隆优势现象在体外实验中同样可见：当细胞在二维培养条件下达到汇合状态，或生长为肿瘤球状体（tumor spheroids）时，即可发生。在此过程中，优势细胞群的生长得到增强。在肿瘤球状体中，这种生长增强现象伴随低表达YAP的细胞凋亡水平升高。克隆优势形成过程中的细胞相互作用，与细胞竞争（cell competition）现象高度相似。RNA测序（RNA-seq）分析显示，该相互作用可诱导致瘤基因的表达，进而可能促进肿瘤生长增强。上述结果表明，肿瘤发生可从异质性肿瘤细胞之间的竞争性相互作用中获益。实验整体设计：对培养于包含两种不同细胞群的不同肿瘤球状体中的细胞系开展基因表达检测，共分析8个样本，未设置重复。