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CDH4 is a novel determinant of osteosarcoma tumorigenesis and metastasis

Oncogene volume 37, pages 3617–3630 (2018)Cite this article

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Abstract

The era of cancer genomics now provides an opportunity to discover novel determinants of osteosarcoma (OS), the most common primary bone cancer in children and adolescents known for its poor prognosis due to lung metastasis. Here, we identify CDH4 amplification in 43.6% of human osteosarcoma using array CGH and demonstrate its critical role in osteosarcoma development and progression. Gain or loss-of-function of CDH4, which encodes R-cadherin, causally impacts multiple features of human OS cells including cell migration and invasion, osteogenic differentiation, and stemness. CDH4 overexpression activates c-Jun via the JNK pathway, while CDH4 knockdown suppresses both tumor xenograft growth and lung colonization. In OS patient specimens, high CDH4 expression associates with lung metastases and poor prognosis. Collectively, our bioinformatics, functional, molecular, and clinical analyses uncover an oncogenic function of CDH4 in osteosarcoma and its relationship with patient outcome.

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References

  1. Biermann JS, Adkins D, Benjamin R, Brigman B, Chow W, Conrad EU 3rd, et al. Bone cancer. J Natl Compr Cancer Netw. 2007;5:420–37.

    Article  Google Scholar 

  2. Briccoli A, Rocca M, Salone M, Guzzardella GA, Balladelli A, Bacci G. High grade osteosarcoma of the extremities metastatic to the lung: long-term results in 323 patients treated combining surgery and chemotherapy, 1985-2005. Surg Oncol. 2010;19:193–9.

    Article  PubMed  Google Scholar 

  3. Luetke A, Meyers PA, Lewis I, Juergens H. Osteosarcoma treatment - where do we stand? A state of the art review. Cancer Treat Rev. 2014;40:523–32.

    Article  PubMed  Google Scholar 

  4. Martin JW, Squire JA, Zielenska M. The genetics of osteosarcoma. Sarcoma. 2012;2012:627254.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Smida J, Xu H, Zhang Y, Baumhoer D, Ribi S, Kovac M, et al. Genome-wide analysis of somatic copy number alterations and chromosomal breakages in osteosarcoma. Int J Cancer. 2017;141:816–28.

    Article  PubMed  CAS  Google Scholar 

  6. Chen X, Bahrami A, Pappo A, Easton J, Dalton J, Hedlund E, et al. Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep. 2014;7:104–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011;144:27–40.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Lorenz S, Baroy T, Sun J, Nome T, Vodak D, Bryne JC, et al. Unscrambling the genomic chaos of osteosarcoma reveals extensive transcript fusion, recurrent rearrangements and frequent novel TP53 aberrations. Oncotarget. 2016;7:5273–88.

    Article  PubMed  Google Scholar 

  9. Lin YH, Jewell BE, Gingold J, Lu L, Zhao R, Wang LL, et al. Osteosarcoma: molecular pathogenesis and iPSC modeling. Trends Mol Med. 2017;23:737–55.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Ozaki T, Schaefer KL, Wai D, Buerger H, Flege S, Lindner N, et al. Genetic imbalances revealed by comparative genomic hybridization in osteosarcomas. Int J Cancer. 2002;102:355–65.

    Article  PubMed  CAS  Google Scholar 

  11. Both J, Wu T, Bras J, Schaap GR, Baas F, Hulsebos TJ. Identification of novel candidate oncogenes in chromosome region 17p11.2-p12 in human osteosarcoma. PLoS ONE. 2012;7:e30907.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Squire JA, Pei J, Marrano P, Beheshti B, Bayani J, Lim G, et al. High-resolution mapping of amplifications and deletions in pediatric osteosarcoma by use of CGH analysis of cDNA microarrays. Genes Chromosomes Cancer. 2003;38:215–25.

    Article  PubMed  CAS  Google Scholar 

  13. Smida J, Baumhoer D, Rosemann M, Walch A, Bielack S, Poremba C, et al. Genomic alterations and allelic imbalances are strong prognostic predictors in osteosarcoma. Clin Cancer Res. 2010;16:4256–67.

    Article  PubMed  CAS  Google Scholar 

  14. Kresse SH, Ohnstad HO, Paulsen EB, Bjerkehagen B, Szuhai K, Serra M, et al. LSAMP, a novel candidate tumor suppressor gene in human osteosarcomas, identified by array comparative genomic hybridization. Genes Chromosomes Cancer. 2009;48:679–93.

    Article  PubMed  CAS  Google Scholar 

  15. Poos K, Smida J, Maugg D, Eckstein G, Baumhoer D, Nathrath M, et al. Genomic heterogeneity of osteosarcoma - shift from single candidates to functional modules. PLoS ONE. 2015;10:e0123082.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Agiostratidou G, Li M, Suyama K, Badano I, Keren R, Chung S, et al. Loss of retinal cadherin facilitates mammary tumor progression and metastasis. Cancer Res. 2009;69:5030–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Miotto E, Sabbioni S, Veronese A, Calin GA, Gullini S, Liboni A, et al. Frequent aberrant methylation of the CDH4 gene promoter in human colorectal and gastric cancer. Cancer Res. 2004;64:8156–9.

    Article  PubMed  CAS  Google Scholar 

  18. Kucharczak J, Charrasse S, Comunale F, Zappulla J, Robert B, Teulon-Navarro I, et al. R-cadherin expression inhibits myogenesis and induces myoblast transformation via Rac1 GTPase. Cancer Res. 2008;68:6559–68.

    Article  PubMed  CAS  Google Scholar 

  19. Kashima T, Nakamura K, Kawaguchi J, Takanashi M, Ishida T, Aburatani H, et al. Overexpression of cadherins suppresses pulmonary metastasis of osteosarcoma in vivo. Int J Cancer. 2003;104:147–54.

    Article  PubMed  CAS  Google Scholar 

  20. Kashima T, Kawaguchi J, Takeshita S, Kuroda M, Takanashi M, Horiuchi H, et al. Anomalous cadherin expression in osteosarcoma. Possible relationships to metastasis and morphogenesis. Am J Pathol. 1999;155:1549–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Tang N, Song WX, Luo J, Haydon RC, He TC. Osteosarcoma development and stem cell differentiation. Clin Orthop Relat Res. 2008;466:2114–30.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Aubin JE. Advances in the osteoblast lineage. Biochem Cell Biol. 1998;76:899–910.

    Article  PubMed  CAS  Google Scholar 

  23. Xie L, Zeng X, Hu J, Chen Q. Characterization of Nestin, a selective marker for bone marrow derived mesenchymal stem cells. Stem Cells Int. 2015;2015:762098.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Kimura R, Ishikawa C, Rokkaku T, Janknecht R, Mori N. Phosphorylated c-Jun and Fra-1 induce matrix metalloproteinase-1 and thereby regulate invasion activity of 143B osteosarcoma cells. Biochim Biophys Acta. 2011;1813:1543–53.

    Article  PubMed  CAS  Google Scholar 

  25. Pohlig F, Ulrich J, Lenze U, Muhlhofer HM, Harrasser N, Suren C, et al. Glucosamine sulfate suppresses the expression of matrix metalloproteinase-3 in osteosarcoma cells in vitro. BMC Complement Altern Med. 2016;16:313.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Bjornland K, Flatmark K, Pettersen S, Aaasen AO, Fodstad O, Maelandsmo GM. Matrix metalloproteinases participate in osteosarcoma invasion. J Surg Res. 2005;127:151–6.

    Article  PubMed  CAS  Google Scholar 

  27. Mathisen B, Lindstad RI, Hansen J, El-Gewely SA, Maelandsmo GM, Hovig E, et al. S100A4 regulates membrane induced activation of matrix metalloproteinase-2 in osteosarcoma cells. Clin Exp Metast. 2003;20:701–11.

    Article  CAS  Google Scholar 

  28. Krueger S, Kellner U, Buehling F, Roessner A. Cathepsin L antisense oligonucleotides in a human osteosarcoma cell line: effects on the invasive phenotype. Cancer Gene Ther. 2001;8:522–8.

    Article  PubMed  CAS  Google Scholar 

  29. Khanna C, Wan X, Bose S, Cassaday R, Olomu O, Mendoza A, et al. The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat Med. 2004;10:182–6.

    Article  PubMed  CAS  Google Scholar 

  30. Gvozdenovic A, Arlt MJ, Campanile C, Brennecke P, Husmann K, Li Y, et al. CD44 enhances tumor formation and lung metastasis in experimental osteosarcoma and is an additional predictor for poor patient outcome. J Bone Miner Res. 2013;28:838–47.

    Article  PubMed  CAS  Google Scholar 

  31. Wheelock MJ, Shintani Y, Maeda M, Fukumoto Y, Johnson KR. Cadherin switching. J Cell Sci. 2008;121:727–35.

    Article  PubMed  CAS  Google Scholar 

  32. Shin CS, Lecanda F, Sheikh S, Weitzmann L, Cheng SL, Civitelli R. Relative abundance of different cadherins defines differentiation of mesenchymal precursors into osteogenic, myogenic, or adipogenic pathways. J Cell Biochem. 2000;78:566–77.

    Article  PubMed  CAS  Google Scholar 

  33. Kawaguchi J, Kii I, Sugiyama Y, Takeshita S, Kudo A. The transition of cadherin expression in osteoblast differentiation from mesenchymal cells: consistent expression of cadherin-11 in osteoblast lineage. J Bone Miner Res. 2001;16:260–9.

    Article  PubMed  CAS  Google Scholar 

  34. Papachristou DJ, Batistatou A, Sykiotis GP, Varakis I, Papavassiliou AG. Activation of the JNK-AP-1 signal transduction pathway is associated with pathogenesis and progression of human osteosarcomas. Bone. 2003;32:364–71.

    Article  PubMed  CAS  Google Scholar 

  35. Fromigue O, Hamidouche Z, Marie PJ. Blockade of the RhoA-JNK-c-Jun-MMP2 cascade by atorvastatin reduces osteosarcoma cell invasion. J Biol Chem. 2008;283:30549–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Bubici C, Papa S. JNK signalling in cancer: in need of new, smarter therapeutic targets. Br J Pharmacol. 2014;171:24–37.

    Article  PubMed  CAS  Google Scholar 

  37. Ibrahim EE, Babaei-Jadidi R, Saadeddin A, Spencer-Dene B, Hossaini S, Abuzinadah M, et al. Embryonic NANOG activity defines colorectal cancer stem cells and modulates through AP1- and TCF-dependent mechanisms. Stem Cells. 2012;30:2076–87.

    Article  PubMed  CAS  Google Scholar 

  38. Gustems M, Woellmer A, Rothbauer U, Eck SH, Wieland T, Lutter D, et al. c-Jun/c-Fos heterodimers regulate cellular genes via a newly identified class of methylated DNA sequence motifs. Nucleic Acids Res. 2014;42:3059–72.

    Article  PubMed  CAS  Google Scholar 

  39. Yoon CH, Kim MJ, Kim RK, Lim EJ, Choi KS, An S, et al. c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells. Oncogene. 2012;31:4655–66.

    Article  PubMed  CAS  Google Scholar 

  40. Murakami T, Igarashi K, Kawaguchi K, Kiyuna T, Zhang Y, Zhao M, et al. Tumor-targeting Salmonella typhimurium A1-R regresses an osteosarcoma in a patient-derived xenograft model resistant to a molecular-targeting drug. Oncotarget. 2017;8:8035–42.

    PubMed  Google Scholar 

  41. Igarashi K, Kawaguchi K, Murakami T, Kiyuna T, Miyake K, Nelson SD, et al. Intra-arterial administration of tumor-targeting Salmonella typhimurium A1-R regresses a cisplatin-resistant relapsed osteosarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model. Cell Cycle. 2017;16:1164–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Lu J, Song G, Tang Q, Yin J, Zou C, Zhao Z, et al. MiR-26a inhibits stem cell-like phenotype and tumor growth of osteosarcoma by targeting Jagged1. Oncogene. 2017;36:231–41.

    Article  PubMed  CAS  Google Scholar 

  43. Kitajima H, Komizu Y, Ichihara H, Goto K, Ueoka R. Hybrid liposomes inhibit tumor growth and lung metastasis of murine osteosarcoma cells. Cancer Med. 2013;2:267–76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Zhang G, Li M, Jin J, Bai Y, Yang C. Knockdown of S100A4 decreases tumorigenesis and metastasis in osteosarcoma cells by repression of matrix metalloproteinase-9. Asian Pac J Cancer Prev. 2011;12:2075–80.

    PubMed  Google Scholar 

  45. Lu J, Song G, Tang Q, Zou C, Han F, Zhao Z, et al. IRX1 hypomethylation promotes osteosarcoma metastasis via induction of CXCL14/NF-kappaB signaling. J Clin Invest. 2015;125:1839–56.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This study is supported by funding from the Canadian Institutes of Health Research (CIHR) and the Canadian Cancer Society Research Institute (CCSRI) to RK, and International Science & Technology Cooperation Program of Guangzhou to JS (201704030008). Q.T. and J.L. are supported by Graduate Student Overseas Study Program of China Scholarship Council. Q.T. is also supported by National Natural Science Foundation of China (81502324), and J.L. is supported by National Postdoctoral Program for Innovative Talents (BX201600196).

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  1. These authors contributed equally: Qinglian Tang, Jinchang Lu.

Authors and Affiliations

  1. Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, M5G 0A3, Canada

    Qinglian Tang, Jinchang Lu, Yang Shao, Yan Chen, Swami Narala, Hui Fang & Rama Khokha

  2. Department of Orthopedic Oncology, First Affiliated Hospital, Sun Yat-Sen University, 510080, Guangzhou, China

    Qinglian Tang, Jinchang Lu, Changye Zou, Huaiyuan Xu, Jin Wang & Jingnan Shen

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Tang, Q., Lu, J., Zou, C. et al. CDH4 is a novel determinant of osteosarcoma tumorigenesis and metastasis. Oncogene 37, 3617–3630 (2018). https://doi.org/10.1038/s41388-018-0231-2

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