Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Targeting mitochondrial translation by inhibiting DDX3: a novel radiosensitization strategy for cancer treatment

Oncogene volume 37, pages 63–74 (2018)Cite this article

Subjects

Abstract

DDX3 is a DEAD box RNA helicase with oncogenic properties. RK-33 is developed as a small-molecule inhibitor of DDX3 and showed potent radiosensitizing activity in preclinical tumor models. This study aimed to assess DDX3 as a target in breast cancer and to elucidate how RK-33 exerts its anti-neoplastic effects. High DDX3 expression was present in 35% of breast cancer patient samples and correlated with markers of aggressiveness and shorter survival. With a quantitative proteomics approach, we identified proteins involved in the mitochondrial translation and respiratory electron transport pathways to be significantly downregulated after RK-33 or DDX3 knockdown. DDX3 localized to the mitochondria and DDX3 inhibition with RK-33 reduced mitochondrial translation. As a consequence, oxygen consumption rates and intracellular ATP concentrations decreased and reactive oxygen species (ROS) increased. RK-33 antagonized the increase in oxygen consumption and ATP production observed after exposure to ionizing radiation and reduced DNA repair. Overall, we conclude that DDX3 inhibition with RK-33 causes radiosensitization in breast cancer through inhibition of mitochondrial translation, which results in reduced oxidative phosphorylation capacity and increased ROS levels, culminating in a bioenergetic catastrophe.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Tanner NK, Linder P . DExD/H box RNA helicases: from generic motors to specific dissociation functions. Mol Cell 2001; 8: 251–262.

    Article  CAS  PubMed  Google Scholar 

  2. Geissler R, Golbik RP, Behrens SE . The DEAD-box helicase DDX3 supports the assembly of functional 80 S ribosomes. Nucleic Acids Res 2012; 40: 4998–5011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Botlagunta M, Vesuna F, Mironchik Y, Raman A, Lisok A, Winnard P Jr et al. Oncogenic role of DDX3 in breast cancer biogenesis. Oncogene 2008; 27: 3912–3922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bol GM, Vesuna F, Xie M, Zeng J, Aziz K, Gandhi N et al. Targeting DDX3 with a small molecule inhibitor for lung cancer therapy. EMBO Mol Med 2015; 7: 648–669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Heerma van Voss MR, Vesuna F, Trumpi K, Brilliant J, Berlinicke C, de Leng W et al. Identification of the DEAD box RNA helicase DDX3 as a therapeutic target in colorectal cancer. Oncotarget 2015; 6: 28312–28326.

    PubMed  Google Scholar 

  6. Wilky BA, Kim C, McCarty G, Montgomery EA, Kammers K, DeVine LR et al. RNA helicase DDX3: a novel therapeutic target in Ewing sarcoma. Oncogene 2016; 35: 2574–2583.

    Article  CAS  PubMed  Google Scholar 

  7. Xie M, Vesuna F, Tantravedi S, Bol GM, Heerma van Voss MR, Nugent K et al. RK-33 radiosensitizes prostate cancer cells by blocking the RNA helicase DDX3. Cancer Res 2016; 76: 6340–6350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li Y, Wang H, Wang Z, Makhija S, Buchsbaum D, LoBuglio A et al. Inducible resistance of tumor cells to tumor necrosis factor-related apoptosis-inducing ligand receptor 2-mediated apoptosis by generation of a blockade at the death domain function. Cancer Res 2006; 66: 8520–8528.

    Article  CAS  PubMed  Google Scholar 

  9. Shih JW, Wang WT, Tsai TY, Kuo CY, Li HK, Wu Lee YH . Critical roles of RNA helicase DDX3 and its interactions with eIF4E/PABP1 in stress granule assembly and stress response. Biochem J 2012; 441: 119–129.

    Article  CAS  PubMed  Google Scholar 

  10. Sun M, Song L, Zhou T, Gillespie GY, Jope RS . The role of DDX3 in regulating Snail. Biochim Biophys Acta 2011; 1813: 438–447.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hagerstrand D, Tong A, Schumacher SE, Ilic N, Shen RR, Cheung HW et al. Systematic interrogation of 3q26 identifies TLOC1 and SKIL as cancer drivers. Cancer Discov 2013; 3: 1044–1057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chen HH, Yu HI, Cho WC, Tarn WY . DDX3 modulates cell adhesion and motility and cancer cell metastasis via Rac1-mediated signaling pathway. Oncogene 2015; 34: 2790–2800.

    Article  CAS  PubMed  Google Scholar 

  13. Kondaskar A, Kondaskar S, Kumar R, Fishbein JC, Muvarak N, Lapidus RG et al. Novel, broad spectrum anti-cancer agents containing the tricyclic 5:7:5-fused diimidazodiazepine ring system. ACS Med Chem Lett 2010; 2: 252–256.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Vellinga TT, Borovski T, de Boer VC, Fatrai S, van Schelven S, Trumpi K et al. SIRT1/PGC1alpha-dependent increase in oxidative phosphorylation supports chemotherapy resistance of colon cancer. Clin Cancer Res 2015; 21: 2870–2879.

    Article  CAS  PubMed  Google Scholar 

  15. Viale A, Corti D, Draetta GF . Tumors and mitochondrial respiration: a neglected connection. Cancer Res 2015; 75: 3685–3686.

    Article  PubMed  Google Scholar 

  16. LeBleu VS, O'Connell JT, Gonzalez Herrera KN, Wikman H, Pantel K, Haigis MC et al. PGC-1alpha mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol 2014; 16: 1001–1015.

    Google Scholar 

  17. Lu CL, Qin L, Liu HC, Candas D, Fan M, Li JJ . Tumor cells switch to mitochondrial oxidative phosphorylation under radiation via mTOR-mediated hexokinase II inhibition—a Warburg-reversing effect. PLoS One 2015; 10: e0121046.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Qin L, Fan M, Candas D, Jiang G, Papadopoulos S, Tian L et al. CDK1 enhances mitochondrial bioenergetics for radiation-induced DNA repair. Cell Rep 2015; 13: 2056–2063.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Croft D, Mundo AF, Haw R, Milacic M, Weiser J, Wu G et al. The Reactome pathway knowledgebase. Nucleic Acids Res 2014; 42: D472–D477.

    Article  CAS  PubMed  Google Scholar 

  20. Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A et al. STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res 2013; 41: D808–D815.

    Article  CAS  PubMed  Google Scholar 

  21. Li Y, D'Aurelio M, Deng JH, Park JS, Manfredi G, Hu P et al. An assembled complex IV maintains the stability and activity of complex I in mammalian mitochondria. J Biol Chem 2007; 282: 17557–17562.

    Article  CAS  PubMed  Google Scholar 

  22. Acin-Perez R, Bayona-Bafaluy MP, Fernandez-Silva P, Moreno-Loshuertos R, Perez-Martos A, Bruno C et al. Respiratory complex III is required to maintain complex I in mammalian mitochondria. Mol Cell 2004; 13: 805–815.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhang X, Fryknas M, Hernlund E, Fayad W, De Milito A, Olofsson MH et al. Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments. Nat Commun 2014; 5: 3295.

    Article  PubMed  Google Scholar 

  24. Pelicano H, Zhang W, Liu J, Hammoudi N, Dai J, Xu RH et al. Mitochondrial dysfunction in some triple-negative breast cancer cell lines: role of mTOR pathway and therapeutic potential. Breast Cancer Res 2014; 16: 434.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Chen Y, McMillan-Ward E, Kong J, Israels SJ, Gibson SB . Oxidative stress induces autophagic cell death independent of apoptosis in transformed and cancer cells. Cell Death Differ 2008; 15: 171–182.

    Article  CAS  PubMed  Google Scholar 

  26. Youle RJ, Narendra DP . Mechanisms of mitophagy. Nat Rev Mol Cell Biol 2011; 12: 9–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Huang Z, Zhou L, Chen Z, Nice EC, Huang C . Stress management by autophagy: implications for chemoresistance. Int J Cancer 2016; 139: 23–32.

    Article  CAS  PubMed  Google Scholar 

  28. Eiermann W, Vallis KA . Locoregional treatments for triple-negative breast cancer. Ann Oncol 2012; 23 (Suppl 6): vi30–vi34.

    Article  PubMed  Google Scholar 

  29. Oshiumi H, Sakai K, Matsumoto M, Seya T . DEAD/H BOX 3 (DDX3) helicase binds the RIG-I adaptor IPS-1 to up-regulate IFN-beta-inducing potential. Eur J Immunol 2010; 40: 940–948.

    Article  CAS  PubMed  Google Scholar 

  30. Antonicka H, Shoubridge EA . Mitochondrial RNA granules are centers for posttranscriptional RNA processing and ribosome biogenesis. Cell Rep 2015; 10: 920–932.

    Article  CAS  PubMed  Google Scholar 

  31. Tu YT, Barrientos A . The human mitochondrial DEAD-Box protein DDX28 resides in RNA granules and functions in mitoribosome assembly. Cell Rep 2015; 10: 854–864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shih JW, Tsai TY, Chao CH, Wu Lee YH . Candidate tumor suppressor DDX3 RNA helicase specifically represses cap-dependent translation by acting as an eIF4E inhibitory protein. Oncogene 2008; 27: 700–714.

    Article  CAS  PubMed  Google Scholar 

  33. Lee CS, Dias AP, Jedrychowski M, Patel AH, Hsu JL, Reed R . Human DDX3 functions in translation and interacts with the translation initiation factor eIF3. Nucleic Acids Res 2008; 36: 4708–4718.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Abaeva IS, Marintchev A, Pisareva VP, Hellen CU, Pestova TV . Bypassing of stems versus linear base-by-base inspection of mammalian mRNAs during ribosomal scanning. EMBO J 2011; 30: 115–129.

    Article  CAS  PubMed  Google Scholar 

  35. Soto-Rifo R, Rubilar PS, Limousin T, de Breyne S, Decimo D, Ohlmann T . DEAD-box protein DDX3 associates with eIF4F to promote translation of selected mRNAs. EMBO J 2012; 31: 3745–3756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Fukumura J, Noguchi E, Sekiguchi T, Nishimoto T . A temperature-sensitive mutant of the mammalian RNA helicase, DEAD-BOX X isoform, DBX, defective in the transition from G1 to S phase. J Biochem 2003; 134: 71–82.

    Article  CAS  PubMed  Google Scholar 

  37. Lai MC, Lee YH, Tarn WY . The DEAD-box RNA helicase DDX3 associates with export messenger ribonucleoproteins as well as tip-associated protein and participates in translational control. Mol Biol Cell 2008; 19: 3847–3858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lai MC, Chang WC, Shieh SY, Tarn WY . DDX3 regulates cell growth through translational control of cyclin E1. Mol Cell Biol 2010; 30: 5444–5453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tarn WY, Chang TH . The current understanding of Ded1p/DDX3 homologs from yeast to human. RNA Biol 2009; 6: 17–20.

    Article  CAS  PubMed  Google Scholar 

  40. Padmanabhan PK, Zghidi-Abouzid O, Samant M, Dumas C, Aguiar BG, Estaquier J et al. DDX3 DEAD-box RNA helicase plays a central role in mitochondrial protein quality control in Leishmania. Cell Death Dis 2016; 7: e2406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chen CY, Chan CH, Chen CM, Tsai YS, Tsai TY, Wu Lee YH et al. Targeted inactivation of murine Ddx3x: essential roles of Ddx3x in placentation and embryogenesis. Hum Mol Genet 2016; 25: 2905–2922.

    CAS  PubMed  Google Scholar 

  42. Koppenol WH, Bounds PL, Dang CV . Otto Warburg's contributions to current concepts of cancer metabolism. Nat Rev Cancer 2011; 11: 325–337.

    Article  CAS  PubMed  Google Scholar 

  43. Weinberg SE, Chandel NS . Targeting mitochondria metabolism for cancer therapy. Nat Chem Biol 2015; 11: 9–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sansone P, Ceccarelli C, Berishaj M, Chang Q, Rajasekhar VK, Perna F et al. Self-renewal of CD133(hi) cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer. Nat Commun 2016; 7: 10442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Jones RA, Robinson TJ, Liu JC, Shrestha M, Voisin V, Ju Y et al. RB1 deficiency in triple-negative breast cancer induces mitochondrial protein translation. J Clin Invest 2016; 126: 3739–3757.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Farnie G, Sotgia F, Lisanti MP . High mitochondrial mass identifies a sub-population of stem-like cancer cells that are chemo-resistant. Oncotarget 2015; 6: 30472–30486.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Matassa DS, Amoroso MR, Lu H, Avolio R, Arzeni D, Procaccini C et al. Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer. Cell Death Differ 2016; 23: 1542–1554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Qin B, Minter-Dykhouse K, Yu J, Zhang J, Liu T, Zhang H et al. DBC1 functions as a tumor suppressor by regulating p53 stability. Cell Rep 2015; 10: 1324–1334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wardman P, Anderson RF, Hodgkiss RJ, Parrick J, Smithen CE, Wallace RG et al. Radiosensitization by non-nitro compounds. Int J Radiat Oncol Biol Phys 1982; 8: 399–401.

    Article  CAS  PubMed  Google Scholar 

  50. Zhang X, Zhou X, Chen R, Zhang H . Radiosensitization by inhibiting complex I activity in human hepatoma HepG2 cells to X-ray radiation. J Radiat Res 2012; 53: 257–263.

    Article  PubMed  Google Scholar 

  51. Skrtic M, Sriskanthadevan S, Jhas B, Gebbia M, Wang X, Wang Z et al. Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia. Cancer Cell 2011; 20: 674–688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Moelans CB, de Weger RA, van Blokland MT, Ezendam C, Elshof S, Tilanus MG et al. HER-2/neu amplification testing in breast cancer by multiplex ligation-dependent probe amplification in comparison with immunohistochemistry and in situ hybridization. Cell Oncol 2009; 31: 1–10.

    CAS  PubMed  Google Scholar 

  53. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 2006; 295: 2492–2502.

    Article  CAS  PubMed  Google Scholar 

  54. Vermeulen JF, van de Ven RA, Ercan C, van der Groep P, van der Wall E, Bult P et al. Nuclear Kaiso expression is associated with high grade and triple-negative invasive breast cancer. PLoS One 2012; 7: e37864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. The Medical Research Involving Human Subjects Act [In Dutch: Wet medisch-wetenschappelijk onderzoek met mensen, WMO]. Burgerlijk Wetboek, Staatsblad van het Koninkrijk der Nederlanden, 1998. Available at: http://wetten.overheid.nl/BWBR0009408/2017-03-01.

  56. Bol GM, Raman V, van der Groep P, Vermeulen JF, Patel AH, van der Wall E et al. Expression of the RNA helicase DDX3 and the hypoxia response in breast cancer. PLoS One 2013; 8: e63548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Angus AG, Dalrymple D, Boulant S, McGivern DR, Clayton RF, Scott MJ et al. Requirement of cellular DDX3 for hepatitis C virus replication is unrelated to its interaction with the viral core protein. J Gen Virol 2010; 91: 122–132.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Chambers AF . MDA-MB-435 and M14 cell lines: identical but not M14 melanoma? Cancer Res 2009; 69: 5292–5293.

    Article  CAS  PubMed  Google Scholar 

  59. Kammers K, Cole RN, Tiengwe C, Ruczinski I . Detecting significant changes in protein abundance. EuPA Open Proteom 2015; 7: 11–19.

    Article  CAS  PubMed  Google Scholar 

  60. Smyth GK . Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 2004; 3: Article 3.

    Article  Google Scholar 

  61. Chen EY, Tan CM, Kou Y, Duan Q, Wang Z, Meirelles GV et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 2013; 14: 128.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Leary SC, Sasarman F . Oxidative phosphorylation: synthesis of mitochondrially encoded proteins and assembly of individual structural subunits into functional holoenzyme complexes. Methods Mol Biol 2009; 554: 143–162.

    Article  CAS  PubMed  Google Scholar 

  63. Rasband WS . ImageJ 2015. U.S. National Institutes of Health: Bethesda, MD, USA.

    Google Scholar 

Download references

Acknowledgements

We thank Bob Cole, Tatiana Boronina and Bob O’ Meally of the Johns Hopkins Mass Spectrometry and Proteomics core facility for their help with the proteomics experiments; Tri Nguyen for his help with interpretation of the electron microscopy images; the Dawson Laboratory at the Johns Hopkins School of Medicine for their help with the mitochondrial translation assay; and Beth Rodgers, who kindly provided us with S35-methionine. This work was financially supported by Utrecht University Alexandre Suerman Stipend (MRHvV), the Dutch Cancer Foundation (UU2013-5851; MRHvV), NIH (R01CA166348 to PTT, R01CA193895 to AL, and R01CA140226 and R01CA131250 to VR), FAMRI (VR) and Safeway (VR).

Author information

Author notes

  1. F Vesuna and G M Bol: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Radiology and Radiological Sciences, Johns Hopkins University, School of Medicine, Baltimore, MD, USA

    M R Heerma van Voss, F Vesuna, G M Bol, S Tantravedi, Y Bergman, D Abou, D Thorek & V Raman

  2. Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands

    M R Heerma van Voss, G M Bol, N ter Hoeve, P J van Diest & V Raman

  3. Department of Cardiology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA

    J Afzal & R Abrahams

  4. Department of Biostatistics, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, USA

    K Kammers

  5. Department of Otolaryngology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA

    M Lehar

  6. Department of Radiation Oncology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA

    R Malek, M Ballew & P T Tran

  7. Wilmer Eye Institute, Johns Hopkins University, School of Medicine, Baltimore, MD, USA

    C Berlinicke, M Yazdankhah & D Sinha

  8. Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA

    A Le

  9. Department of Oncology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA

    A Le, P T Tran, P J van Diest & V Raman

  10. Department of Urology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA

    P T Tran

Authors
  1. M R Heerma van Voss
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F Vesuna
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G M Bol
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Afzal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Tantravedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y Bergman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K Kammers
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Lehar
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R Malek
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M Ballew
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. N ter Hoeve
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. D Abou
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. D Thorek
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. C Berlinicke
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. M Yazdankhah
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. D Sinha
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. A Le
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. R Abrahams
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. P T Tran
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. P J van Diest
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. V Raman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to V Raman.

Ethics declarations

Competing interests

VR and PTT have received a patent for the use of RK-33 as a radiosensitizer (US 8,518,901). VR, GMB and PJvD have received a patent for the use of DDX3 as a cancer biomarker (US 9,322,831). PJvD, PTT and VR are on the advisory board of Natsar Pharmaceuticals.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Heerma van Voss, M., Vesuna, F., Bol, G. et al. Targeting mitochondrial translation by inhibiting DDX3: a novel radiosensitization strategy for cancer treatment. Oncogene 37, 63–74 (2018). https://doi.org/10.1038/onc.2017.308

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2017.308

This article is cited by

Search

Advanced search

Quick links