High-grade serous ovarian carcinoma (HGSC) is associated with late-stage disease presentation and poor prognosis, with limited understanding of early transformation events. Our study presents a comprehensive analysis of tumor progression and organ-specific metastatic dissemination to identify hypoxia-associated molecular, cellular, and histological alterations during HGSC tumor growth. HE staining and subsequent histological assessment of tumor volume-based categories revealed recapitulation of numerous clinical features, including the prevalence of >0.0625≤0.5cm3 volume tumors and metastatic spread by orthotopic xenografts. The constant evolution of the tissue architecture concerning increased hyaluronic acid deposition, tumor vasculature, necrosis, altered proliferative potential, and gland forming ability of the tumor cells was identified. Flow cytometry and label chase-based molecular profiling across the tumor regenerative hierarchy identified the hypoxia-vasculogenic niche and the hybrid epithelial-mesenchymal tumor-cell state as determinants of self-renewal capabilities of progenitors and cancer stem cells (CSCs). A regulatory network and mathematical model based on tumor histology and molecular signatures predicted hypoxia-inducible factor 1-alpha (HIF1A) as a central node connecting epithelial-mesenchymal transition, metabolic and necrotic pathways in HGSC tumors. Thus, our findings provide a temporal resolution of hypoxia-associated events that sculpt HGSC tumor growth, and an in-depth understanding of it may aid in the early detection and treatment of HGSC.


中文翻译：

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高级别浆液性卵巢癌的多步肿瘤生长模型识别缺氧相关特征

高级别浆液性卵巢癌 (HGSC) 与晚期疾病表现和不良预后相关，对早期转化事件的了解有限。我们的研究对肿瘤进展和器官特异性转移传播进行了全面分析，以识别 HGSC 肿瘤生长过程中与缺氧相关的分子、细胞和组织学改变。HE 染色和随后对基于肿瘤体积的分类的组织学评估揭示了许多临床特征的概括，包括 >0.0625≤0.5cm3 体积肿瘤的患病率和原位异种移植物的转移扩散。确定了与增加的透明质酸沉积、肿瘤脉管系统、坏死、改变的增殖潜力和肿瘤细胞的腺体形成能力有关的组织结构的不断演变。跨肿瘤再生层次的流式细胞术和基于标签追踪的分子谱分析确定了缺氧血管生成生态位和混合上皮间充质肿瘤细胞状态是祖细胞和癌症干细胞 (CSC) 自我更新能力的决定因素。基于肿瘤组织学和分子特征的调控网络和数学模型预测缺氧诱导因子 1-α (HIF1A) 是连接 HGSC 肿瘤中上皮-间质转化、代谢和坏死通路的中心节点。因此，我们的研究结果提供了塑造 HGSC 肿瘤生长的缺氧相关事件的时间分辨率，并且对它的深入了解可能有助于 HGSC 的早期检测和治疗。