Blocking tumor-educated MSC paracrine activity halts osteosarcoma progression

Serena Rubina Baglio, Tonny Lagerweij, Maria Pérez-Lanzón, Xuan Dung Ho, Nicolas Léveillé, Sonia A. Melo, Anne Marie Cleton-Jansen, Ekaterina S. Jordanova, Laura Roncuzzi, Michelina Greco, Monique A.J. Van Eijndhoven, Giulia Grisendi, Massimo Dominici, Roberta Bonafede, Sinead M. Lougheed, Tanja D. De Gruijl, Nicoletta Zini, Silvia Cervo, Agostino Steffan, Vincenzo CanzonieriAare Martson, Katre Maasalu, Sulev Köks, Tom Wurdinger, Nicola Baldini, D. Michiel Pegtel

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Purpose: Human osteosarcoma is a genetically heterogeneous bone malignancy with poor prognosis despite the employment of aggressive chemotherapy regimens. Because druggable driver mutations have not been established, dissecting the interactions between osteosarcoma cells and supporting stroma may provide insights into novel therapeutic targets. Experimental Design: By using a bioluminescent orthotopic xenograft mouse model of osteosarcoma, we evaluated the effect of tumor extracellular vesicle (EV)–educated mesenchymal stem cells (TEMSC) on osteosarcoma progression. Characterization and functional studies were designed to assess the mechanisms underlying MSC education. Independent series of tissue specimens were analyzed to corroborate the preclinical findings, and the composition of patient serum EVs was analyzed after isolation with size-exclusion chromatography. Results: We show that EVs secreted by highly malignant osteosarcoma cells selectively incorporate a membrane-associated form of TGFb, which induces proinflammatory IL6 production by MSCs. TEMSCs promote tumor growth, accompanied with intratumor STAT3 activation and lung metastasis formation, which was not observed with control MSCs. Importantly, intravenous administration of the anti-IL6 receptor antibody tocilizumab abrogated the tumor-promoting effects of TEMSCs. RNA-seq analysis of human osteosarcoma tissues revealed a distinct TGFb-induced prometastatic gene signature. Tissue microarray immunostaining indicated active STAT3 signaling in human osteosarcoma, consistent with the observations in TEMSC-treated mice. Finally, we isolated pure populations of EVs from serum and demonstrated that circulating levels of EV-associated TGFb are increased in osteosarcoma patients. Conclusions: Collectively, our findings suggest that TEMSCs promote osteosarcoma progression and provide the basis for testing IL6- and TGFb-blocking agents as new therapeutic options for osteosarcoma patients.

Original languageEnglish
Pages (from-to)3721-3733
Number of pages13
JournalClinical Cancer Research
Volume23
Issue number14
DOIs
Publication statusPublished - 15 Jul 2017

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