The fundamental steps in high-grade serous ovarian cancer (HGSOC) initiation are unclear presenting critical barriers in prevention and early detection of this deadly disease. Current models propose that fallopian tube epithelial (FTE) cells transform into serous tubal intraepithelial carcinoma (STIC) precursor lesions and subsequently HGSOC. Here we report that an epigenetically altered mesenchymal stem cell niche, termed high risk MSC (hrMSC), exists prior to STIC lesion formation. hrMSCs are enriched in STIC stroma and contribute to a stromal ‘field effect’ extending beyond the borders of STIC lesion. hrMSCs promote DNA damage in FTE cells while also fostering FTE cell survival. hrMSCs induce malignant transformation of FTE resulting in metastatic cancer in vivo, indicating hrMSCs promote cancer initiation. hrMSCs are significantly enriched in BRCA1/2 mutation carriers and increase with age. Combined, these findings indicate that hrMSCs can incite ovarian cancer initiation and have important implications for ovarian cancer detection and prevention.

中文翻译：

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衰老和 BRCA 突变的基质细胞驱动上皮细胞转化

高级别浆液性卵巢癌 （HGSOC） 发生的基本步骤尚不清楚，这在预防和早期发现这种致命疾病方面存在重大障碍。目前的模型表明，输卵管上皮 （FTE） 细胞转化为浆液性输卵管上皮内癌 （STIC） 前体病变，随后转化为 HGSOC。在这里，我们报道了在 STIC 病变形成之前存在表观遗传改变的间充质干细胞生态位，称为高危 MSC （hrMSC）。hrMSC 富含 STIC 基质，并有助于延伸到 STIC 病变边界之外的基质“场效应”。hrMSC 促进 FTE 细胞中的 DNA 损伤，同时也促进 FTE 细胞存活。hrMSC 诱导 FTE 的恶性转化，导致体内转移性癌症，表明 hrMSC 促进癌症的发生。hrMSC 在 BRCA1/2 突变携带者中显著富集，并随着年龄的增长而增加。综上所述，这些发现表明 hrMSC 可以诱发卵巢癌，并对卵巢癌的检测和预防具有重要意义。