Editors' ChoiceCancer

Exosomes deliver resistance

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Science Signaling  24 May 2016:
Vol. 9, Issue 429, pp. ec123
DOI: 10.1126/scisignal.aag1853

Exosomes are increasingly recognized for their contribution to cancer progression by mediating intercellular communication between tumor cells and between the tumor and its surrounding stromal tissue. Among their contents, exosomes carry an abundance of RNAs, particularly microRNA (miRNA). Qu et al. found that drug-resistant renal cancer cells conferred resistance to sensitive cells through exosome-mediated transfer of a long noncoding RNA (lncRNA) that competes with tumor-suppressive miRNAs. Renal cell carcinoma (RCC) has a high rate of recurrence and intrinsic resistance to the drug sunitinib, a receptor tyrosine kinase (RTK) inhibitor. A sunitinib-resistant population of RCC cells was generated using serial passage xenografts in sunitinib-treated mice. Through microarray analysis and various assays in the RCC cell lines and in patient-derived xenografts in mice, increased abundance of lncARSR was identified as a critical mediator of sunitinib resistance. The abundance of lncARSR was also increased in the culture medium from sunitinib-resistant RCC cells. The pretherapy abundance of lncARSR in the plasma and tumor tissue of patients negatively correlated with clinical response to sunitinib and progression-free survival. Sunitinib-resistant RCC cells released lncARSR in exosomes, and its packaging into exosomes involved the ribonucleoprotein hnRNPA2B1. Bioinformatics and cellular assays revealed that lncARSR bound the miRNAs miR-34 and miR-449 and increased the abundance of AXL and c-MET in recipient cells, a result consistent with the increased abundance of AXL and c-MET detected in sunitinib-resistant RCC xenografts and relapsed tumors in patients. A small-molecule inhibitor of both AXL and c-MET resensitized lncARSR-expressing cells to sunitinib in culture and restored sunitinib efficacy in vivo. The findings reveal that lncARSR acts as a sponge for tumor-suppressive miRNAs in RCC and indicate potential strategies by which to improve sunitinib therapy in patients.

L. Qu, J. Ding, C. Chen, Z.-J. Wu, B. Liu, Y. Gao, W. Chen, F. Liu, W. Sun, X.-F. Li, X. Wang, Y. Wang, Z.-Y. Xu, L. Gao, Q. Yang, B. Xu, Y.-M. Li, Z.-Y. Fang, Z.-P. Xu, Y. Bao, D.-S. Wu, X. Miao, H.-Y. Sun, Y.-H. Sun, H.-Y. Wang, L.-H. Wang, Exosome-transmitted lncARSR promotes sunitinib resistance in renal cancer by acting as a competing endogenous RNA. Cancer Cell 29, 653–668 (2016). [PubMed]

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