PO.PR02.02 · 预防研究

纤毛细胞驱动输卵管上皮中关键的STING介导的肿瘤抑制

Ciliated cells drive critical STING-mediated tumor suppression in fallopian tube epithelium

编号 7640 展板 27 时间 4/22 09:00–12:00 区域 Section 36 主讲 Analisa DiFeo, PhD

分会场 Cancer and Cancer Related Alterations, Detection Approaches, and Molecular Characterization

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作者与单位 Authors & Affiliations

Jose Colina¹, Maria Sol Recouvreux², Alex Sobeck³, Benjamin K. Johnson⁴, Yinzhi Lin⁵, Sreeja C. Sekhar⁶, Rita A. Avelar⁵, Gabriela Rivera⁵, Yali Zhai⁶, amber fatima⁵, Paula DiBenedetto⁵, Justin Baldassarre⁵, Grace McIntyre⁵, Jessica Teitel⁵, Michele Cusato⁶, Harini Ram⁵, Noah Puleo⁶, Karan Bedi⁵, Jane Miglo⁷, Hui Shen⁸, Dafydd G. Thomas⁹, Jutta Huvila¹⁰, Dawn R. Cochrane¹¹, Ronny I. Drapkin¹², Yu Lei¹³, Joanna E. Burdette¹⁴, David G. Huntsman¹⁵, Kathleen Cho⁶, Sandra Orsulic¹⁶, Analisa DiFeo⁵

¹George Washington University, Washington, DC,²UCLA, Los Angeles, CA,³Washington University in St. Louis, St. Louis, MO,⁴Van Andel Research Institute, Grand Rapids, MI,⁵University of Michigan, Ann Arbor, MI,⁶University of Michigan Medical School, Ann Arbor, MI,⁷University of Chicago, Chicago, IL,⁸Graduate Student, Van Andel Research Institute, Grand Rapids, MI,⁹Lecturer/Research Investigator, University of Michigan, Ann Arbor, MI,¹⁰University of Turku, Turku, Finland,¹¹BC Cancer Agency, Vancouver, BC, Canada,¹²University of Pennsylvania, Merion Station, PA,¹³MD Anderson Cancer Center, Houston, TX,¹⁴Assistant Professor, Dept. of Medical Chemistry, University of Illinois at Chicago, Chicago, IL,¹⁵University of British Columbia, Vancouver, BC, Canada,¹⁶David Geffen School of Medicine, Los Angeles, CA

摘要 Abstract

中文摘要

减轻输卵管上皮（FTE）的DNA损伤对于预防输卵管-卵巢高级别浆液性癌（HGSC）至关重要。在此，我们证明STING在FTE的纤毛细胞中大量表达，并作为一种关键的免疫非依赖性肿瘤抑制因子发挥作用。利用患者样本、小鼠模型和类器官系统，我们证明纤毛细胞对排卵相关的基因毒性应激发起了双重保护性反应：内源性STING驱动的凋亡，以及通过分泌TNFα对邻近受损分泌细胞的外源性清除。这种监视机制显著限制了上皮微环境内DNA损伤的累积。至关重要的是，尽管这些机制对于维持稳态和减少基因组不稳定性至关重要，但它们无法影响p53缺陷的前体病变，因为内源性和外源性促凋亡过程均依赖于功能正常的p53信号。本研究揭示了STING高表达纤毛输卵管细胞此前未被认识的、免疫非依赖性的作用，即作为基因组完整性的主动守护者，其缺失为HGSC的起始创造了一个允许性微环境。利益冲突声明：R.D.在VOC Health和Repare Therapeutics的科学顾问委员会任职。DGH曾是Imagia Canexia Health的创始人兼首席医疗官。其他作者声明无竞争性利益。

查看英文原文 English abstract

Mitigating DNA damage in the fallopian tube epithelium (FTE) is essential for preventing tubo-ovarian high-grade serous carcinoma (HGSC). Here we demonstrate that STING is abundantly expressed in the ciliated cells of the FTE and functions as a critical immune-independent tumor suppressor. Using patient samples, mouse models, and organoid systems, we demonstrate that ciliated cells mount a dual protective response to ovulation-associated genotoxic stress: intrinsic STING-driven apoptosis and extrinsic clearance of neighboring damaged secretory cells via TNFalpha secretion. This surveillance mechanism markedly limits DNA damage accumulation within the epithelial microenvironment. Crucially, while these mechanisms are vital for maintaining homeostasis and reducing genomic instability, they fail to impact p53-deficient precursor lesions as both intrinsic and extrinsic pro-apoptotic processes rely on functional p53 signaling. This study uncovers a previously unrecognized, immune-independent role for STING-high ciliated fallopian tube cells as active guardians of genomic integrity, whose loss creates a permissive niche for HGSC initiation. CONFLICT OF INTEREST STATEMENT: R.D. serves on the scientific advisory board of VOC Health and Repare Therapeutics. DGH is a previous founder and Chief Medical Officer of Imagia Canexia Health. The other authors declare that they have no competing interests.

利益披露 Disclosure

J. Colina, None.. M. Recouvreux, None.. A. Sobeck, None.. Y. Lin, None.. G. Rivera, None.. A. fatima, None.. P. DiBenedetto, None.. J. Baldassarre, None.. H. Ram, None.. K. Bedi, None.. J. Miglo, None.. A. DiFeo, None.

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