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Cancer cells exploit an orphan RNA to drive metastatic progression

Abstract

Here we performed a systematic search to identify breast-cancer-specific small noncoding RNAs, which we have collectively termed orphan noncoding RNAs (oncRNAs). We subsequently discovered that one of these oncRNAs, which originates from the 3′ end of TERC, acts as a regulator of gene expression and is a robust promoter of breast cancer metastasis. This oncRNA, which we have named T3p, exerts its prometastatic effects by acting as an inhibitor of RISC complex activity and increasing the expression of the prometastatic genes NUPR1 and PANX2. Furthermore, we have shown that oncRNAs are present in cancer-cell-derived extracellular vesicles, raising the possibility that these circulating oncRNAs may also have a role in non–cell autonomous disease pathogenesis. Additionally, these circulating oncRNAs present a novel avenue for cancer fingerprinting using liquid biopsies.

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Fig. 1: Discovery, annotation and validation of cancer-specific oncRNAs in breast cancer.
Fig. 2: The oncRNA T3p is associated with breast cancer progression.
Fig. 3: T3p regulates gene expression and drives metastatic progression.
Fig. 4: T3p biogenesis and function.
Fig. 5: T3p-mediated inhibition of miR-10b and miR-378c results in overexpression of metastasis promoters NUPR1 and PANX2.
Fig. 6: Systematic profiling of oncRNAs in the extracellular compartment.

Data Availability

All sequencing data generated for this study has been deposited in the Gene Expression Omnibus under the accession number GSE114366.

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Acknowledgements

We thank D. Ruggero, D. Erle, F. Feng, S. Tavazoie and S. Tavazoie for reading earlier versions of this manuscript; D. Erle and P. Godoy for providing early access to their serum smRNA profiles; B. Hann and the Preclinical Therapeutics core as well as the Laboratory Animal Resource Center (LARC); S. Kilinc for her assistance with extracellular vesicle size analysis; F. Fattahi for helpful discussions; and J. Massagué for providing cell lines. We are also grateful for the genomic data contributed by the TCGA Research Network, including donors and researchers. We acknowledge the UCSF Center for Advanced Technology (CAT) for high-throughput sequencing and other genomic analyses; and support from our colleagues at the Breast Oncology Program (Helen Diller Family Comprehensive Cancer Center). This work was supported by the NIH (R01GM123977 and R00CA194077), Friends for an Earlier Breast Cancer Test, the American Cancer Society (130920-RSG-17-114-01-RMC) and the Goldberg-Benioff Fund in Translational Research. S.Z. was supported through the HHMI Medical Research Fellowship. J.X.Y. is an NSF GRFP fellow. A.G. was supported by the CDMRP Breast Cancer Research Program W81XWH-12-1-0272 and W81XWH-16-1-0603.

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H.G. conceived and designed the study. L.F. and S.Z. performed RNA isolations and prepared smRNA-seq libraries. J.X.Y. performed FACS analysis. S.Z., B.C. and H.G. performed mouse experiments. H.G. performed computational analyses. A.G. and A.Y.Z. contributed data from PDX models. L.F., S.Z. and H.G. wrote the manuscript. H.G. supervised the project.

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Correspondence to Hani Goodarzi.

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Fish, L., Zhang, S., Yu, J.X. et al. Cancer cells exploit an orphan RNA to drive metastatic progression. Nat Med 24, 1743–1751 (2018). https://doi.org/10.1038/s41591-018-0230-4

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