Sinha Saptarshi, Callow Brennan W, Farfel Alex P, Roy Suchismita, Chen Siyi, Masotti Maria, Rajendran Shrila, Buschhaus Johanna M, Espinoza Celia R, Luker Kathryn E, Ghosh Pradipta, Luker Gary D
Department of Cellular and Molecular Medicine, School of Medicine, UCSD, La Jolla, California, USA.
Center for Molecular Imaging, Department of Radiology.
J Clin Invest. 2024 Oct 31;134(24):e170953. doi: 10.1172/JCI170953.
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.
雌激素受体阳性（ER+）乳腺癌通常会扩散至骨髓，在骨髓中，其与间充质基质细胞（MSC）的相互作用塑造了疾病进程。我们通过肿瘤-MSC共培养对这些相互作用进行建模，并使用整合的转录组-蛋白质组-网络分析工作流程来识别接触诱导变化的全面目录。来自MSC的条件培养基无法重现直接接触在癌细胞中诱导产生的基因和蛋白质，其中一些是“借用”的，另一些是肿瘤内在的。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。生物信息学将其中一个“借用”成分CCDC88A/GIV列为优先研究对象，CCDC88A/GIV是一种多模块转移相关蛋白，最近被认为与驱动癌症的一个标志——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，经由隧道纳米管将GIV蛋白转移至缺乏GIV的ER+乳腺癌细胞。在GIV阴性乳腺癌细胞中单独恢复GIV的表达，可重现接触共培养中约20%的“借用”和内在基因诱导模式；赋予对抗雌激素药物的抗性；并增强肿瘤扩散。这些发现为MSC→肿瘤细胞间的细胞转运提供了多组学见解，并验证了一种这样的候选蛋白GIV从“有者”（MSC）向“无者”（ER+乳腺癌）的转运如何调控侵袭性疾病状态。
