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Inactivation of Capicua drives cancer metastasis

Nature Genetics volume 49, pages 87–96 (2017)Cite this article

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Abstract

Metastasis is the leading cause of death in people with lung cancer, yet the molecular effectors underlying tumor dissemination remain poorly defined. Through the development of an in vivo spontaneous lung cancer metastasis model, we show that the developmentally regulated transcriptional repressor Capicua (CIC) suppresses invasion and metastasis. Inactivation of CIC relieves repression of its effector ETV4, driving ETV4-mediated upregulation of MMP24, which is necessary and sufficient for metastasis. Loss of CIC, or an increase in levels of its effectors ETV4 and MMP24, is a biomarker of tumor progression and worse outcomes in people with lung and/or gastric cancer. Our findings reveal CIC as a conserved metastasis suppressor, highlighting new anti-metastatic strategies that could potentially improve patient outcomes.

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Figure 1: Our in vivo orthotopic model identifies novel effectors of lung cancer metastasis.
Figure 2: CIC is altered in advanced-stage LA.
Figure 3: Inactivation of CIC de-represses an ETV4–MMP24 pro-metastatic circuit.
Figure 4: CIC effector MMP24 drives lung cancer metastasis.
Figure 5: MAPK pathway activation functionally suppresses CIC.
Figure 6: The CIC–ETV4–MMP24 metastatic axis is deregulated in gastric cancer.
Figure 7: CIC suppresses cancer metastasis.

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Acknowledgements

R.A.O. was supported by the A.P. Giannini Foundation and NIHT32CA177555-01. T.G.B. acknowledges support from NIH Director's New Innovator Award DP2 CA174497, NIH/NCI RO1 CA169338, and the Pew-Stewart Foundation Trusts. We thank B. Hann (UCSF Preclinical Therapeutics Core) for helpful discussions. The lentiviral GFP-Luc vector was a kind gift from M. Jensen (Seattle Children's Research Institute, Seattle, Washington, USA).

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Authors and Affiliations

  1. Department of Medicine, University of California, San Francisco, San Francisco, California, USA

    Ross A Okimoto, Victor R Olivas, Wei Wu, Beatrice Gini, Asmin Tulpule, Collin M Blakely & Trever G Bivona

  2. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA

    Ross A Okimoto, Wei Wu, Beatrice Gini, Saurabh Asthana, Gorjan Hrustanovic, Jennifer Flanagan, Asmin Tulpule, Collin M Blakely & Trever G Bivona

  3. Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany

    Frank Breitenbuecher & Martin Schuler

  4. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA

    Matan Hofree

  5. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Matan Hofree

  6. Clovis Oncology Inc., San Francisco, California, USA

    Henry J Haringsma & Andrew D Simmons

  7. Foundation Medicine, Cambridge, Massachusetts, USA

    Kyle Gowen, James Suh, Vincent A Miller & Siraj Ali

  8. German Cancer Consortium (DKTK), Heidelberg, Germany

    Martin Schuler

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Contributions

R.A.O. designed and performed the experiments, analyzed the data, and wrote the manuscript. R.A.O., F.B., V.R.O., and B.G. performed in vivo studies. M.H. and W.W. performed TCGA analysis. K.G., J.S., V.A.M., and S. Ali provided lung cancer data sets. S. Asthana, J.F., H.J.H., and A.D.S. analyzed RNA-seq and CNA data. G.H., A.T., C.M.B., and M.S. provided clinical samples. T.G.B. directed the project, designed and analyzed experiments, and wrote the manuscript.

Corresponding author

Correspondence to Trever G Bivona.

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Competing interests

H.J.H. and A.D.S. are employees of Clovis Oncology. K.G., J.S., V.A.M., and S. Ali are employees of Foundation Medicine. T.G.B. is a consultant to Novartis, Astellas, Array Biopharma, Ariad, Teva, and Astrazeneca, and has received research funding from Ignyta.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–15 and Supplementary Tables 1 and 5 (PDF 41965 kb)

Supplementary Table 2

Top 1,500 differentially expressed genes between H1975 M1 (CIC null) and H1975 M1 with reconstituted CIC expression (XLSX 137 kb)

Supplementary Table 3a

Top 1,000 differentially expressed genes between H1975 and H1975 M1 cells. Ranked by P value. Fold change and log2 fold change are also provided. (XLSX 117 kb)

Supplementary Table 3b

Top 1,000 differentially expressed genes between H1975 and H1975 M2 cells. Ranked by P value. Fold change and log2 fold change are also provided. (XLSX 121 kb)

Supplementary Table 4

267 putative CIC response genes. (XLSX 82 kb)

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Okimoto, R., Breitenbuecher, F., Olivas, V. et al. Inactivation of Capicua drives cancer metastasis. Nat Genet 49, 87–96 (2017). https://doi.org/10.1038/ng.3728

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