Aged and BRCA mutated stromal cells drive epithelial cell transformation.

IF 29.7 1区医学 Q1 ONCOLOGY

Cancer discovery Pub Date : 2025-03-14 DOI:10.1158/2159-8290.CD-24-0805

Geyon L Garcia, Taylor Orellana, Grace Gorecki, Leonard Frisbie, Roja Baruwal, Swathi Suresh, Ester Goldfeld, Ian Beddows, Ian P MacFawn, Ananya K Britt, Macy M Hale, Amal Taher Elhaw, Brian R Isett, Nadine Hempel, Riyue Bao, Hui Shen, Ronald J Buckanovich, Toren Finkel, Ronny Drapkin, T Rinda Soong, Tullia C Bruno, Huda I Atiya, Lan G Coffman

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引用次数: 0

Abstract

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.

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高级别浆液性卵巢癌（HGSOC）发病的基本步骤尚不清楚，这对预防和早期检测这种致命疾病造成了严重障碍。目前的模型认为，输卵管上皮（FTE）细胞转变为浆液性输卵管上皮内癌（STIC）前体病变，随后转变为高级别浆液性卵巢癌。hrMSCs富集于STIC基质中，并促成基质 "场效应"，延伸至STIC病变边界之外。hrMSCs 能促进 FTE 细胞的 DNA 损伤，同时还能促进 FTE 细胞的存活。hrMSCs 能诱导 FTE 恶性转化，导致体内转移性癌症，这表明 hrMSCs 能促进癌症的发生。这些研究结果表明，hrMSCs 可诱导卵巢癌的发生，对卵巢癌的检测和预防具有重要意义。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer discovery ONCOLOGY-

CiteScore

22.90

自引率

1.40%

发文量

838

审稿时长

6-12 weeks

期刊介绍： Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.