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Breast cancers that disseminate to bone marrow acquire aggressive phenotypes through CX43-related tumor-stroma tunnels.
The Journal of Clinical Investigation ( IF 13.3 ) 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

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.

中文翻译:


播散至骨髓的乳腺癌通过 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+) 乳腺癌通常播散到骨髓,在那里与间充质基质细胞 (MSC) 的相互作用塑造了疾病轨迹。我们用肿瘤-MSC 共培养物模拟了这些相互作用,并使用集成的转录组-蛋白质组-网络分析工作流程来确定接触诱导变化的全面目录。来自 MSC 的条件培养基未能概括通过直接接触在癌细胞中诱导的基因和蛋白质,其中一些是借来的,另一些是肿瘤固有的。蛋白质-蛋白质相互作用网络揭示了 “借用 ” 和 “内在” 成分之间的丰富连接组。生物信息学优先考虑了“借来的”成分之一,CCDC88A/GIV,这是一种多模块化转移相关蛋白质,最近被认为与驱动癌症的一个标志,即生长信号自主性有关。MSC 通过连接蛋白 (Cx) 43 促进的细胞间转运,通过隧道纳米管将 GIV 蛋白转移到 ER+ 乳腺癌细胞(缺乏 GIV)。在 GIV 阴性乳腺癌细胞中单独恢复 GIV 从接触共培养物中复制了大约 20% 的“借来的”和“内在的”基因诱导模式;赋予对抗雌激素药物的耐药性;和增强肿瘤播散。研究结果为MSC→肿瘤细胞细胞间运输提供了多组学见解,并验证了一种候选者GIV如何从富人(MSCs)到穷人(ER+乳腺癌)的运输协调侵袭性疾病状态。
更新日期:2024-10-31
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