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:

Distinct cellular origin and genetic requirement of Hedgehog-Gli in postnatal rhabdomyosarcoma genesis

Oncogene volume 33, pages 5370–5378 (2014)Cite this article

Subjects

Abstract

Dysregulation of the Hedgehog (Hh)-Gli signaling pathway is implicated in a variety of human cancers, including basal cell carcinoma (BCC), medulloblastoma (MB) and embryonal rhabdhomyosarcoma (eRMS), three principle tumors associated with human Gorlin syndrome. However, the cells of origin of these tumors, including eRMS, remain poorly understood. In this study, we explore the cell populations that give rise to Hh-related tumors by specifically activating Smoothened (Smo) in both Hh-producing and -responsive cell lineages in postnatal mice. Interestingly, we find that unlike BCC and MB, eRMS originates from the stem/progenitor populations that do not normally receive active Hh signaling. Furthermore, we find that the myogenic lineage in postnatal mice is largely Hh quiescent and that Pax7-expressing muscle satellite cells are not able to give rise to eRMS upon Smo or Gli1/2 overactivation in vivo, suggesting that Hh-induced skeletal muscle eRMS arises from Hh/Gli quiescent non-myogenic cells. In addition, using the Gli1 null allele and a Gli3 repressor allele, we reveal a specific genetic requirement for Gli proteins in Hh-induced eRMS formation and provide molecular evidence for the involvement of Sox4/11 in eRMS cell survival and differentiation.

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

Similar content being viewed by others

References

  1. McMahon AP, Ingham PW, Tabin CJ . Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol 2003; 53: 1–114.

    Article  CAS  PubMed  Google Scholar 

  2. Jiang J, Hui CC . Hedgehog signaling in development and cancer. Dev Cell 2008; 15: 801–812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Barakat MT, Humke EW, Scott MP . Learning from Jekyll to control Hyde: Hedgehog signaling in development and cancer. Trends Mol Med 2010; 16: 337–348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lum L, Beachy PA . The Hedgehog response network: sensors, switches, and routers. Science 2004; 304: 1755–1759.

    Article  CAS  PubMed  Google Scholar 

  5. Hooper JE, Scott MP . Communicating with Hedgehogs. Nat Rev Mol Cell Biol 2005; 6: 306–317.

    Article  CAS  PubMed  Google Scholar 

  6. Hui CC, Angers S . Gli Proteins in Development and Disease. Annu Rev Cell Dev Biol 2011; 27: 23.21–23.25.

    Article  Google Scholar 

  7. Stecca B, Ruiz IAA . Context-dependent regulation of the GLI code in cancer by HEDGEHOG and non-HEDGEHOG signals. J Mol Cell Biol 2010; 2: 84–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gorlin RJ . Nevoid basal-cell carcinoma syndrome. Medicine (Baltimore) 1987; 66: 98–113.

    Article  CAS  Google Scholar 

  9. Rubin LL, de Sauvage FJ . Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov 2006; 5: 1026–1033.

    Article  CAS  PubMed  Google Scholar 

  10. Teglund S, Toftgard R . Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim Biophys Acta 2010; 1805: 181–208.

    CAS  PubMed  Google Scholar 

  11. Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 1996; 272: 1668–1671.

    Article  CAS  PubMed  Google Scholar 

  12. Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996; 85: 841–851.

    Article  CAS  PubMed  Google Scholar 

  13. Oro AE, Higgins KM, Hu Z, Bonifas JM, Epstein EH Jr., Scott MP . Basal cell carcinomas in mice overexpressing sonic hedgehog. Science 1996; 276: 817–821.

    Article  Google Scholar 

  14. Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C et al. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 1998; 391: 90–92.

    Article  CAS  PubMed  Google Scholar 

  15. Aszterbaum M, Epstein J, Oro A, Douglas V, LeBoit PE, Scott MP et al. Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice. Nat Med 1999; 5: 1285–1291.

    Article  CAS  PubMed  Google Scholar 

  16. Grachtchouk M, Mo R, Yu S, Zhang X, Sasaki H, Hui CC et al. Basal cell carcinomas in mice overexpressing Gli2 in skin. Nat Genet 2000; 24: 216–217.

    Article  CAS  PubMed  Google Scholar 

  17. Mao J, Ligon KL, Rakhlin EY, Thayer SP, Bronson RT, Rowitch D et al. A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway. Cancer Res 2006; 66: 10171–10178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Schuller U, Heine VM, Mao J, Kho AT, Dillon AK, Han YG et al. Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell 2008; 14: 123–134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wechsler-Reya RJ, Scott MP . Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron 1999; 22: 103–114.

    Article  CAS  PubMed  Google Scholar 

  20. Rowitch DH, S-Jacques B, Lee SM, Flax JD, Snyder EY, McMahon AP . Sonic hedgehog regulates proliferation and inhibits differentiation of CNS precursor cells. J Neurosci 1999; 19: 8954–8965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Oliver TG, Read TA, Kessler JD, Mehmeti A, Wells JF, Huynh TT et al. Loss of patched and disruption of granule cell development in a pre-neoplastic stage of medulloblastoma. Development 2005; 132: 2425–2439.

    Article  CAS  PubMed  Google Scholar 

  22. Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS, Eden C et al. Subtypes of medulloblastoma have distinct developmental origins. Nature 2010; 468: 1095–1099.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Youssef KK, Van Keymeulen A, Lapouge G, Beck B, Michaux C, Achouri Y et al. Identification of the cell lineage at the origin of basal cell carcinoma. Nat Cell Biol 2010; 12: 299–305.

    Article  CAS  PubMed  Google Scholar 

  24. Ridky TW, Khavari PA . The hair follicle bulge stem cell niche resists transformation by the hedgehog pathway. Cell Stem Cell 2010; 6: 292–294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Grachtchouk M, Pero J, Yang SH, Ermilov AN, Michael LE, Wang A et al. Basal cell carcinomas in mice arise from hair follicle stem cells and multiple epithelial progenitor populations. J Clin Invest 2011; 121: 1768–1781.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang GY, Wang J, Mancianti ML, Epstein EH Jr. . Basal cell carcinomas arise from hair follicle stem cells in Ptch1(+/−) mice. Cancer Cell 2011; 19: 114–124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Pappo AS . Rhabdomyosarcoma and other soft tissue sarcomas of childhood. Curr Opin Oncol 1995; 7: 361–366.

    Article  CAS  PubMed  Google Scholar 

  28. Merlino G, Helman LJ . Rhabdomyosarcoma—working out the pathways. Oncogene 1999; 18: 5340–5348.

    Article  CAS  PubMed  Google Scholar 

  29. Breneman JC, Lyden E, Pappo AS, Link MP, Anderson JR, Parham DM et al. Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma—a report from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 2003; 21: 78–84.

    Article  PubMed  Google Scholar 

  30. Hettmer S, Wagers AJ . Muscling in: uncovering the origins of rhabdomyosarcoma. Nat Med 2010; 16: 171–173.

    Article  CAS  PubMed  Google Scholar 

  31. Roberts WM, Douglass EC, Peiper SC, Houghton PJ, Look AT . Amplification of the gli gene in childhood sarcomas. Cancer Res 1989; 49: 5407–5413.

    CAS  PubMed  Google Scholar 

  32. Bridge JA, Liu J, Weibolt V, Baker KS, Perry D, Kruger R et al. Novel genomic imbalances in embryonal rhabdomyosarcoma revealed by comparative genomic hybridization and fluorescence in situ hybridization: an intergroup rhabdomyosarcoma study. Genes Chromosomes Cancer 2000; 27: 337–344.

    Article  CAS  PubMed  Google Scholar 

  33. Bridge JA, Liu J, Qualman SJ, Suijkerbuijk R, Wenger G, Zhang J et al. Genomic gains and losses are similar in genetic and histologic subsets of rhabdomyosarcoma, whereas amplification predominates in embryonal with anaplasia and alveolar subtypes. Genes Chromosomes Cancer 2002; 33: 310–321.

    Article  CAS  PubMed  Google Scholar 

  34. Tostar U, Malm CJ, Meis-Kindblom JM, Kindblom LG, Toftgard R, Unden AB . Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development. J Pathol 2006; 208: 17–25.

    Article  CAS  PubMed  Google Scholar 

  35. Zibat A, Missiaglia E, Rosenberger A, Pritchard-Jones K, Shipley J, Hahn H et al. Activation of the hedgehog pathway confers a poor prognosis in embryonal and fusion gene-negative alveolar rhabdomyosarcoma. Oncogene 2010; 29: 6323–6330.

    Article  CAS  PubMed  Google Scholar 

  36. Hayashi S, McMahon AP . Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. Dev Biol 2002; 244: 305–318.

    Article  CAS  PubMed  Google Scholar 

  37. Harfe BD, Scherz PJ, Nissim S, Tian H, McMahon AP, Tabin CJ . Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities. Cell 2004; 118: 517–528.

    Article  CAS  PubMed  Google Scholar 

  38. Ahn S, Joyner AL . Dynamic changes in the response of cells to positive hedgehog signaling during mouse limb patterning. Cell 2004; 118: 505–516.

    Article  CAS  PubMed  Google Scholar 

  39. Lee J, Platt KA, Censullo P, Ruiz i Altaba A . Gli1 is a target of Sonic hedgehog that induces ventral neural tube development. Development 1997; 124: 2537–2552.

    CAS  PubMed  Google Scholar 

  40. Bai CB, Auerbach W, Lee JS, Stephen D, Joyner AL . Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development 2002; 129: 4753–4761.

    Article  CAS  PubMed  Google Scholar 

  41. Ahn S, Joyner AL . In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog. Nature 2005; 437: 894–897.

    Article  CAS  PubMed  Google Scholar 

  42. Brownell I, Guevara E, Bai CB, Loomis CA, Joyner AL . Nerve-derived sonic hedgehog defines a niche for hair follicle stem cells capable of becoming epidermal stem cells. Cell Stem Cell 2011; 8: 552–565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Soriano P . Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet 1999; 21: 70–71.

    Article  CAS  PubMed  Google Scholar 

  44. Tiffin N, Williams RD, Shipley J, Pritchard-Jones K . PAX7 expression in embryonal rhabdomyosarcoma suggests an origin in muscle satellite cells. Br J Cancer 2003; 89: 327–332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hettmer S, Liu J, Miller CM, Lindsay MC, Sparks CA, Guertin DA et al. Sarcomas induced in discrete subsets of prospectively isolated skeletal muscle cells. Proc Natl Acad Sci USA 2011; 108: 20002–20007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Rubin BP, Nishijo K, Chen HI, Yi X, Schuetze DP, Pal R et al. Evidence for an unanticipated relationship between undifferentiated pleomorphic sarcoma and embryonal rhabdomyosarcoma. Cancer Cell 2011; 19: 177–191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Asakura A, Hirai H, Kablar B, Morita S, Ishibashi J, Piras BA et al. Increased survival of muscle stem cells lacking the MyoD gene after transplantation into regenerating skeletal muscle. Proc Natl Acad Sci USA 2007; 104: 16552–16557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hirai H, Verma M, Watanabe S, Tastad C, Asakura Y, Asakura A . MyoD regulates apoptosis of myoblasts through microRNA-mediated down-regulation of Pax3. J Cell Biol 2010; 191: 347–365.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lepper C, Conway SJ, Fan CM . Adult satellite cells and embryonic muscle progenitors have distinct genetic requirements. Nature 2009; 460: 627–631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Vokes SA, Ji H, McCuine S, Tenzen T, Giles S, Zhong S et al. Genomic characterization of Gli-activator targets in sonic hedgehog-mediated neural patterning. Development 2007; 134: 1977–1989.

    Article  CAS  PubMed  Google Scholar 

  51. Kimura H, Stephen D, Joyner A, Curran T . Gli1 is important for medulloblastoma formation in Ptc1+/- mice. Oncogene 2005; 24: 4026–4036.

    Article  CAS  PubMed  Google Scholar 

  52. Vokes SA, Ji H, Wong WH, McMahon AP . A genome-scale analysis of the cis-regulatory circuitry underlying sonic hedgehog-mediated patterning of the mammalian limb. Genes Dev 2008; 22: 2651–2663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Wang B, Fallon JF, Beachy PA . Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 2000; 100: 423–434.

    Article  CAS  PubMed  Google Scholar 

  54. Lauth M, Bergstrom A, Shimokawa T, Toftgard R . Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc Natl Acad Sci USA 2007; 104: 8455–8460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Brennan DJ, Ek S, Doyle E, Drew T, Foley M, Flannelly G et al. The transcription factor Sox11 is a prognostic factor for improved recurrence-free survival in epithelial ovarian cancer. Eur J Cancer 2009; 45: 1510–1517.

    Article  CAS  PubMed  Google Scholar 

  56. Liao YL, Sun YM, Chau GY, Chau YP, Lai TC, Wang JL et al. Identification of SOX4 target genes using phylogenetic footprinting-based prediction from expression microarrays suggests that overexpression of SOX4 potentiates metastasis in hepatocellular carcinoma. Oncogene 2008; 27: 5578–5589.

    Article  CAS  PubMed  Google Scholar 

  57. Liu P, Ramachandran S, Ali Seyed M, Scharer CD, Laycock N, Dalton WB et al. Sex-determining region Y box 4 is a transforming oncogene in human prostate cancer cells. Cancer Res 2006; 66: 4011–4019.

    Article  CAS  PubMed  Google Scholar 

  58. Medina PP, Castillo SD, Blanco S, Sanz-Garcia M, Largo C, Alvarez S et al. The SRY-HMG box gene, SOX4, is a target of gene amplification at chromosome 6p in lung cancer. Hum Mol Genet 2009; 18: 1343–1352.

    Article  CAS  PubMed  Google Scholar 

  59. Kasper M, Jaks V, Are A, Bergstrom A, Schwager A, Barker N et al. Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes. Proc Natl Acad Sci USA 2011; 108: 4099–4104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hatley ME, Tang W, Garcia MR, Finkelstein D, Millay DP, Liu N et al. A mouse model of rhabdomyosarcoma originating from the adipocyte lineage. Cancer Cell 2012; 22: 536–546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Koleva M, Kappler R, Vogler M, Herwig A, Fulda S, Hahn H . Pleiotropic effects of sonic hedgehog on muscle satellite cells. Cell Mol Life Sci 2005; 62: 1863–1870.

    Article  CAS  PubMed  Google Scholar 

  62. Tostar U, Toftgard R, Zaphiropoulos PG, Shimokawa T . Reduction of human embryonal rhabdomyosarcoma tumor growth by inhibition of the hedgehog signaling pathway. Genes Cancer 2010; 1: 941–951.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bhattaram P, Penzo-Mendez A, Sock E, Colmenares C, Kaneko KJ, Vassilev A et al. Organogenesis relies on SoxC transcription factors for the survival of neural and mesenchymal progenitors. Nat Commun 2010; 1: 1–12.

    Article  CAS  Google Scholar 

  64. Lee CJ, Appleby VJ, Orme AT, Chan WI, Scotting PJ . Differential expression of SOX4 and SOX11 in medulloblastoma. J Neurooncol 2002; 57: 201–214.

    Article  PubMed  Google Scholar 

  65. Gerber AN, Wilson CW, Li YJ, Chuang PT . The hedgehog regulated oncogenes Gli1 and Gli2 block myoblast differentiation by inhibiting MyoD-mediated transcriptional activation. Oncogene 2007; 26: 1122–1136.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work is supported by grants from American Cancer Society (120376-RSG-11-040-01-DDC), Charles H Hood Foundation and Worcester Foundation for Biomedical Research to JM. APM is supported by a grant from NIH (NS033642). The authors thank Drs Michael Rudnicki (University of Ottawa) and Amy Wagers (Joslin Diabetes Center) for providing cell isolation protocols, Joe Vaughan and Zhiwei Pang for technical support, and members of the Mao lab for helpful discussion.

Author information

Author notes

  1. J K Brooks

    Present address: 6Current address: Division of Hematology/Oncology, Children's Hospital, Boston, MA 02115, USA.,

  2. M Rajurkar, H Huang and J L Cotton: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA

    M Rajurkar, H Huang, J L Cotton, J K Brooks & J Mao

  2. Department of Histology & Embryology, Xiangya School of Medicine, Central South University, Changsha, PR China

    H Huang

  3. Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA

    J Sicklick

  4. Department of Stem Cell Biology and Regenerative Medicine, Broad-CIRM Center for Regenerative Medicine and Stem Cell Research, WM Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

    A P McMahon

Authors
  1. M Rajurkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J L Cotton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J K Brooks
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Sicklick
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A P McMahon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Mao.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rajurkar, M., Huang, H., Cotton, J. et al. Distinct cellular origin and genetic requirement of Hedgehog-Gli in postnatal rhabdomyosarcoma genesis. Oncogene 33, 5370–5378 (2014). https://doi.org/10.1038/onc.2013.480

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.480

Keywords

This article is cited by

Search

Advanced search

Quick links