研究动态
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复制压力和缺陷的检查点使得输卵管上皮细胞成为高级别浆液性卵巢癌潜在的起动因素。

Replication stress and defective checkpoints make fallopian tube epithelial cells putative drivers of high-grade serous ovarian cancer.

发表日期:2023 Sep 19
作者: Pamoda Galhenage, Yunlan Zhou, Erica Perry, Brenda Loc, Kelly Fietz, Sonia Iyer, Ferenc Reinhardt, Tiego Da Silva, Vladimir Botchkarev, Jie Chen, Christopher P Crum, Robert A Weinberg, Shailja Pathania
来源: Cell Reports

摘要:

临床和分子证据表明,高级别浆液性卵巢癌(HGSOC)主要起源于输卵管,而不是卵巢表面。然而,这种偏好的原因尚不清楚。我们的研究突出了输卵管上皮细胞(FTE)和卵巢表面上皮细胞(OSE)之间的显著差异,为FTE作为HGSOC起源点提供了分子基础。与OSE不同,FTE展示了增强的复制应激(RS),受阻叉修复受损,G2/M检查点无效以及增加的肿瘤发生性。BRCA1杂合子加剧了这些缺陷,导致RS抑制半失功能和侵袭性肿瘤表型。人体和小鼠切片检查显示RS标记物53BP1主要积聚在输卵管中,尤其是在丝状端部。此外,绝经状态影响RS水平。我们的研究为FTE作为HGSOC起源点提供了机制解释,研究了BRCA1杂合子对其的影响,并为早期HGSOC驱动基因的靶向提供了基础。 版权所有©2023 作者。Elsevier Inc.发表并保留所有权利。
Clinical and molecular evidence indicates that high-grade serous ovarian cancer (HGSOC) primarily originates from the fallopian tube, not the ovarian surface. However, the reasons for this preference remain unclear. Our study highlights significant differences between fallopian tube epithelial (FTE) and ovarian surface epithelial (OSE) cells, providing the molecular basis for FTEs as site of origin of HGSOC. FTEs, unlike OSEs, exhibit heightened replication stress (RS), impaired repair of stalled forks, ineffective G2/M checkpoint, and increased tumorigenicity. BRCA1 heterozygosity exacerbates these defects, resulting in RS suppression haploinsufficiency and an aggressive tumor phenotype. Examination of human and mouse sections reveals buildup of the RS marker 53BP1 primarily in the fallopian tubes, particularly at the fimbrial ends. Furthermore, menopausal status influences RS levels. Our study provides a mechanistic rationale for FTE as the site of origin for HGSOC, investigates the impact of BRCA1 heterozygosity, and lays the groundwork for targeting early HGSOC drivers.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.