Breast cancers that disseminate to bone marrow acquire aggressive phenotypes through CX43-related tumor-stroma tunnels.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Journal of Clinical Investigation Pub Date : 2024-10-31 DOI:10.1172/JCI170953
Saptarshi Sinha, Brennan W Callow, Alex P Farfel, Suchismita Roy, Siyi Chen, Maria Masotti, Shrila Rajendran, Johanna M Buschhaus, Celia R Espinoza, Kathryn E Luker, Pradipta Ghosh, Gary D Luker
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Abstract

Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions with tumor-MSC co-cultures and used an integrated transcriptome-proteome-network-analyses workflow to identify a comprehensive catalog of contact-induced changes. Conditioned media from MSCs failed to recapitulate genes and proteins, some borrowed and others tumor-intrinsic, induced in cancer cells by direct contact. Protein-protein interaction networks revealed the rich connectome between 'borrowed' and 'intrinsic' components. Bioinformatics prioritized one of the 'borrowed' components, CCDC88A/GIV, a multi-modular metastasis-related protein that has recently been implicated in driving a hallmark of cancer, growth signaling autonomy. MSCs transferred GIV protein to ER+ breast cancer cells (that lack GIV) through tunnelling nanotubes via connexin (Cx)43-facilitated intercellular transport. Reinstating GIV alone in GIV-negative breast cancer cells reproduced approximately 20% of both the 'borrowed' and the 'intrinsic' gene induction patterns from contact co-cultures; conferred resistance to anti-estrogen drugs; and enhanced tumor dissemination. Findings provide a multiomic insight into MSC→tumor cell intercellular transport and validate how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.

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扩散到骨髓的乳腺癌通过与 CX43 相关的肿瘤基质隧道获得侵袭性表型。
雌激素受体阳性(ER+)乳腺癌通常会扩散到骨髓,在骨髓中与间充质基质细胞(MSCs)的相互作用会影响疾病的发展轨迹。我们用肿瘤-间充质干细胞共培养物模拟了这些相互作用,并使用转录组-蛋白质组-网络-分析综合工作流程确定了接触诱导变化的综合目录。间充质干细胞的条件培养基未能再现癌细胞通过直接接触诱导的基因和蛋白质,其中一些是借用的,另一些则是肿瘤内在的。蛋白质-蛋白质相互作用网络揭示了 "借用 "和 "内在 "成分之间丰富的连接组。生物信息学确定了其中一个 "借入 "成分的优先级,即CCDC88A/GIV,它是一种与转移相关的多模块蛋白,最近被证实与癌症的一个标志--生长信号自主性--有关。间充质干细胞通过连接蛋白(Cx)43促进的细胞间运输,通过隧道式纳米管将GIV蛋白转移到ER+乳腺癌细胞(缺乏GIV)。在 GIV 阴性的乳腺癌细胞中单独重新植入 GIV,可重现接触共培养中约 20% 的 "借用 "和 "内在 "基因诱导模式;赋予细胞对抗雌激素药物的抗性;并增强肿瘤的扩散。研究结果为间叶干细胞→肿瘤细胞的细胞间转运提供了多组学视角,并验证了GIV这种候选基因如何从 "有"(间叶干细胞)转运到 "无"(ER+乳腺癌),从而协调侵袭性疾病状态。
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来源期刊
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
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