Crescenzo Massaro, Hilal N Sensoy, Manon Mulders, Celine De Schrijver, Cristina Gómez-Martín, Juan Simon Nieto, Tonny Lagerweij, Alisha Atmopawiro, Jennifer Pérez-Boza, Maarten Bebelman, Leontien Bosch, Simone Foderaro, Mafalda Neves Ferreira, Monique A J van Eijndhoven, Jan R T van Weering, Carmela Dell'Aversana, Lucia Altucci, Cemile Dilara Savci-Heijink, Niels W C J van de Donk, Cristina Giorgio, Laura Brandolini, Marcello Allegretti, Dirk Michiel Pegtel, Serena Rubina Baglio
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引用次数: 0
摘要
目的：耐药性是骨癌治疗中的一个主要临床障碍，似乎在很大程度上是由人们不甚了解的微环境因素驱动的。最近的证据表明，具有炎症特征的间充质干细胞（iMSCs）这一独特亚群发挥着关键作用，但它们的起源和功能仍未得到探索。我们证明癌症分泌的细胞外囊泡（EVs）会引发iMSCs的发展，从而阻碍体内的治疗反应，并着手确定对抗其功能的策略：实验设计：在骨肉瘤异位移植小鼠模型中评估了iMSCs在治疗抵抗中的作用。分析了EV诱导的间充质干细胞转录组改变，并与骨肉瘤和多发性骨髓瘤患者活检组织的scRNA-seq数据进行了比较。功能测试确定了驱动 iMSC 发育的 EV 成分。我们评估了临床药物在阻断iMSC诱导的体内抗药性方面的疗效：结果：我们发现，iMSCs 是通过与癌症 EV 相互作用而诱导的，并且完全削弱了 TGFb 信号抑制的抗转移效果。重要的是，EV诱导的iMSCs忠实地再现了多发性骨髓瘤和骨肉瘤患者活检组织中富集的基质细胞的炎性单细胞RNA特征。从机理上讲，癌症 EV 通过两种不同的机制发挥作用。EV相关的TGFb会诱导IL6的产生，而EV-RNA货物则会增强TLR3介导的趋化因子的产生。我们发现，用拉达立新和托珠单抗同时阻断EV激活的下游通路可破坏转移的形成并克服iMSC诱导的抗药性：我们的观察结果表明，iMSC 是导致耐药性的主要因素，揭示了 EV 是 iMSC 发展的生理触发器，并强调了一种很有前景的联合策略，可改善骨癌患者的治疗反应。
Purpose: Therapy resistance is a major clinical hurdle in bone cancer treatment and seems to be largely driven by poorly understood microenvironmental factors. Recent evidence suggests a critical role for a unique subpopulation of mesenchymal stem cells with inflammatory features (iMSC), though their origin and function remained unexplored. We demonstrate that cancer-secreted extracellular vesicles (EV) trigger the development of iMSCs, which hinder therapy response in vivo, and set out to identify strategies to counteract their function.
Experimental design: The role of iMSCs in therapy resistance was evaluated in an orthotopic xenograft mouse model of osteosarcoma. EV-induced alterations of the MSC transcriptome were analyzed and compared with single-cell RNA sequencing data of biopsies from patients with osteosarcoma and multiple myeloma. Functional assays identified EV components driving iMSC development. We assessed the efficacy of clinical drugs in blocking iMSC-induced resistance in vivo.
Results: We found that iMSCs are induced by interaction with cancer EVs and completely abrogate the antimetastatic effect of TGFβ signaling inhibition. Importantly, EV-induced iMSCs faithfully recapitulate the inflammatory single-cell RNA signature of stromal cells enriched in biopsies from patients with multiple myeloma and osteosarcoma. Mechanistically, cancer EVs act through two distinct mechanisms. EV-associated TGFβ induces IL6 production, whereas the EV-RNA cargo enhances TLR3-mediated chemokine production. We reveal that simultaneous blockade of downstream EV-activated pathways with ladarixin and tocilizumab disrupts metastasis formation and overcomes iMSC-induced resistance.
Conclusions: Our observations establish iMSCs as major contributors to drug resistance, reveal EVs as triggers of iMSC development, and highlight a promising combination strategy to improve therapy response in patients with bone cancer.
期刊介绍：
Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.
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