Joseph Sayali, Zhang Xingyuan, Droby Gaith N, Wu Di, Bae-Jump Victoria, Lyons Scott, Mordant Angie, Mills Allie, Herring Laura, Rushing Blake, Bowser Jessica L, Vaziri Cyrus
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC 27710, USA.
Cell Rep. 2025 Jan 28;44(1):115104. doi: 10.1016/j.celrep.2024.115104. Epub 2024 Dec 20.
The molecular underpinnings of high-grade endometrial carcinoma (HGEC) metastatic growth and survival are poorly understood. Here, we show that ascites-derived and primary tumor HGEC cell lines in 3D spheroid culture faithfully recapitulate key features of malignant peritoneal effusion and exhibit fundamentally distinct transcriptomic, proteomic, and metabolomic landscapes compared with conventional 2D monolayers. Using a genetic screening platform, we identify MAPK14 (which encodes the protein kinase p38α) as a specific requirement for HGEC in spheroid culture. MAPK14/p38α has broad roles in programming the phosphoproteome, transcriptome, and metabolome of HGEC spheroids, yet has negligible impact on monolayer cultures. MAPK14 promotes tumorigenicity in vivo and is specifically required to sustain a sub-population of spheroid cells that is enriched in cancer stemness markers. Therefore, spheroid growth of HGEC activates unique biological programs, including p38α signaling, that cannot be captured using 2D culture models and are highly relevant to malignant disease pathology.
高级别子宫内膜癌（HGEC）转移生长和存活的分子基础仍知之甚少。在此，我们表明，3D球体培养中的腹水来源和原发性肿瘤HGEC细胞系忠实地再现了恶性腹腔积液的关键特征，并且与传统的2D单层细胞相比，呈现出根本不同的转录组、蛋白质组和代谢组图谱。使用基因筛选平台，我们确定MAPK14（编码蛋白激酶p38α）是球体培养中HGEC的特定需求。MAPK14/p38α在编程HGEC球体的磷酸蛋白质组、转录组和代谢组方面具有广泛作用，但对单层培养的影响可忽略不计。MAPK14在体内促进肿瘤发生，并且是维持富含癌症干性标志物的球体细胞亚群所特别需要的。因此，HGEC的球体生长激活了独特的生物学程序，包括p38α信号传导，这些程序无法使用2D培养模型捕获，并且与恶性疾病病理学高度相关。
