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.

  • Review Article
  • Published:

Probing for a deeper understanding of rhabdomyosarcoma: insights from complementary model systems

Nature Reviews Cancer volume 15, pages 426–439 (2015)Cite this article

Subjects

Key Points

  • Rhabdomyosarcoma (RMS) is a soft tissue malignancy composed of neoplastic cells that morphologically resemble skeletal muscle-lineage precursor cells. High-risk RMS has a dismal prognosis, and treatments for this condition have not improved for three decades now.

  • RMS is a heterogeneous disease composed of four subtypes. Embryonal RMS (ERMS), the most common subtype, associates with various tumour-promoting signalling pathways (for example, RAS and Hedgehog) and/or loss of tumour surveillance (for example, TP53 mutations). Pleomorphic RMS is very aggressive and occurs during the sixth and seventh decades of life. Spindle cell/sclerosing RMS affects both children and adults, with favourable and unfavourable prognoses, respectively. Alveolar RMS (ARMS), which is notoriously aggressive, is a genetically distinct disease driven by the PAX3–FOXO1 and PAX7–FOXO1 chimeric oncoproteins that are unique to ARMS.

  • Understanding the cell (or cells) of origin for RMS is complex, reflecting the fact that multiple precursor cells can give rise to RMS in mouse models.

  • To relieve a bottleneck that has existed in the design of new RMS therapies, an impressive array of new RMS model systems, spanning the evolutionary spectrum from flies to fish to mammals, have recently been developed; these new models have proven successful in uncovering new pathogenic mechanisms of RMS.

  • Moreover, RMS gene discovery prompted by these diverse yet remarkably complementary model systems is inspiring new possibilities for targeted RMS therapy.

  • These models also point to viable approaches for the genetic and molecular dissection of other clinically problematic non-RMS sarcomas.

Abstract

Rhabdomyosarcoma (RMS) is a mesenchymal malignancy composed of neoplastic primitive precursor cells that exhibit histological features of myogenic differentiation. Despite intensive conventional multimodal therapy, patients with high-risk RMS typically suffer from aggressive disease. The lack of directed therapies against RMS emphasizes the need to further uncover the molecular underpinnings of the disease. In this Review, we discuss the notable advances in the model systems now available to probe for new RMS-targetable pathogenetic mechanisms, and the possibilities for enhanced RMS therapeutics and improved clinical outcomes.

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: PAX3 and PAX7 fusion proteins.
Figure 2: RMS model systems along the myogenic continuum.
Figure 3: Complementary models of RMS and their advantages.
Figure 4: RMS pathways for targeted therapy.

Similar content being viewed by others

References

  1. Sultan, I., Qaddoumi, I., Yaser, S., Rodriguez-Galindo, C. & Ferrari, A. Comparing adult and pediatric rhabdomyosarcoma in the surveillance, epidemiology and end results program, 1973 to 2005: an analysis of 2,600 patients. J. Clin. Oncol. 27, 3391–3397 (2009).

    Article  PubMed  Google Scholar 

  2. Goldblum, J., Folpe, A. & Weiss, S. in Enzinger and Weiss's Soft Tissue Tumors (eds Goldblum, J., Folpe, A. & Weiss, S.) 601–638 (Elsevier Saunders, 2014).

    Google Scholar 

  3. Wexler, L., Meyer, W. & Helman, L. in Principles and Practice of Pediatric Oncology (eds Pizzo, P. & Poplack, D.) 923–953 (Lippincott WIlliams & Wilkins, 2011).

    Google Scholar 

  4. Barr, F. G., Montgomery, E. A., Nascimento, A. F., & Parham, D. M. in WHO Classification of Tumours of Soft Tissue and Bone (eds Fletcher, C. D. M., Bridge, J. A., Hogendoorn, P. & Mertens, F.) 123–135 (IARC, 2013).

    Google Scholar 

  5. Parham, D. M. & Barr, F. G. in WHO Classification of Tumours of Soft Tissue and Bone (eds Fletcher, C. D. M., Bridge, J. A., Hogendoorn, P. & Mertens, F.) 130–132 (IARC, 2013).

    Google Scholar 

  6. Montgomery, E. A. & Barr, F. G. in WHO Classification of Tumours of Soft Tissue and Bone (eds Fletcher, C. D. M., Bridge, J. A., Hogendoorn, P. & Mertens, F.) 132–133 (IARC, 2013).

    Google Scholar 

  7. Nascimento, A. F. & Barr, F. G. in WHO Classification of Tumours of Soft Tissue and Bone (eds Fletcher, C. D. M., Bridge, J. A., Hogendoorn, P. & Mertens, F.) 134–135 (IARC, 2013).

    Google Scholar 

  8. Mosquera, J. M. et al. Recurrent NCOA2 gene rearrangements in congenital/infantile spindle cell rhabdomyosarcoma. Genes Chromosomes Cancer 52, 538–550 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Agaram, N. P. et al. Recurrent MYOD1 mutations in pediatric and adult sclerosing and spindle cell rhabdomyosarcomas: evidence for a common pathogenesis. Genes Chromosomes Cancer 53, 779–787 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kohsaka, S. et al. A recurrent neomorphic mutation in MYOD1 defines a clinically aggressive subset of embryonal rhabdomyosarcoma associated with PI3K–AKT pathway mutations. Nat. Genet. 46, 595–600 (2014). References 9 and 10 were the first to identify the recurrent somatic MYOD1L122R mutation in RMS (ERMS and spindle cell/sclerosing RMS) and associate this mutation with poor clinical outcomes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Shapiro, D. N., Sublett, J. E., Li, B., Downing, J. R. & Naeve, C. W. Fusion of PAX3 to a member of the forkhead family of transcription factors in human alveolar rhabdomyosarcoma. Cancer Res. 53, 5108–5112 (1993).

    CAS  PubMed  Google Scholar 

  12. Galili, N. et al. Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat. Genet. 5, 230–235 (1993).

    Article  CAS  PubMed  Google Scholar 

  13. Davis, R. J., D'Cruz, C. M., Lovell, M. A., Biegel, J. A. & Barr, F. G. Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcoma. Cancer Res. 54, 2869–2872 (1994).

    CAS  PubMed  Google Scholar 

  14. Xia, S. J., Pressey, J. G. & Barr, F. G. Molecular pathogenesis of rhabdomyosarcoma. Cancer Biol. Ther. 1, 97–104 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Sumegi, J. et al. Recurrent t(2;2) and t(2;8) translocations in rhabdomyosarcoma without the canonical PAX–FOXO1 fuse PAX3 to members of the nuclear receptor transcriptional coactivator (NCOA) family. Genes Chromosomes Cancer 49, 224–236 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Wachtel, M. et al. Gene expression signatures identify rhabdomyosarcoma subtypes and detect a novel t(2;2)(q35;p23) translocation fusing PAX3 to NCOA1. Cancer Res. 64, 5539–5545 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Shern, J. F. et al. Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. Cancer Discov. 4, 216–231 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sorensen, P. H. et al. PAX3–FKHR and PAX7–FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group. J. Clin. Oncol. 20, 2672–2679 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Williamson, D. et al. Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. J. Clin. Oncol. 28, 2151–2158 (2010). This paper reports that the clinical and genetic features of RMS tumours with alveolar-type histology but negative for the PAX3–FOXO1 or PAX7–FOXO1 fusion (fusion-negative ARMS) are indistinguishable from RMS.

    Article  PubMed  Google Scholar 

  20. Sokolowski, E., Turina, C. B., Kikuchi, K., Langenau, D. M. & Keller, C. Proof-of-concept rare cancers in drug development: the case for rhabdomyosarcoma. Oncogene 33, 1877–1889 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Hettmer, S. et al. Rhabdomyosarcoma: current challenges and their implications for developing therapies. Cold Spring Harb. Perspect. Med. 4, a025650 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Keller, C. & Guttridge, D. C. Mechanisms of impaired differentiation in rhabdomyosarcoma. FEBS J. 280, 4323–4334 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Davicioni, E. et al. Molecular classification of rhabdomyosarcoma — genotypic and phenotypic determinants of diagnosis: a report from the Children's Oncology Group. Am. J. Pathol. 174, 550–564 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Shukla, N. et al. Oncogene mutation profiling of pediatric solid tumors reveals significant subsets of embryonal rhabdomyosarcoma and neuroblastoma with mutated genes in growth signaling pathways. Clin. Cancer Res. 18, 748–757 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. Chen, X. et al. Targeting oxidative stress in embryonal rhabdomyosarcoma. Cancer Cell 24, 710–724 (2013). Together, references 17 and 25 report comprehensive whole-genome sequence projects for RMS, which reveal that ERMS has a markedly higher background mutation rate than ARMS, and that RAS activating mutations associate with intermediate- and high-risk disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hinson, A. R. et al. Human rhabdomyosarcoma cell lines for rhabdomyosarcoma research: utility and pitfalls. Front. Oncol. 3, 183 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Linardic, C. M., Downie, D. L., Qualman, S., Bentley, R. C. & Counter, C. M. Genetic modeling of human rhabdomyosarcoma. Cancer Res. 65, 4490–4495 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Olson, E. N., Spizz, G. & Tainsky, M. A. The oncogenic forms of N-ras or H-ras prevent skeletal myoblast differentiation. Mol. Cell. Biol. 7, 2104–2111 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Stratton, M. R., Fisher, C., Gusterson, B. A. & Cooper, C. S. Detection of point mutations in N-ras and K-ras genes of human embryonal rhabdomyosarcomas using oligonucleotide probes and the polymerase chain reaction. Cancer Res. 49, 6324–6327 (1989).

    CAS  PubMed  Google Scholar 

  30. Schaaf, G. et al. Silencing of SPRY1 triggers complete regression of rhabdomyosarcoma tumors carrying a mutated RAS gene. Cancer Res. 70, 762–771 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Martinelli, S. et al. RAS signaling dysregulation in human embryonal rhabdomyosarcoma. Genes Chromosomes Cancer 48, 975–982 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Paulson, V. et al. High-resolution array CGH identifies common mechanisms that drive embryonal rhabdomyosarcoma pathogenesis. Genes Chromosomes Cancer 50, 397–408 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Aoki, Y. et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat. Genet. 37, 1038–1040 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Kratz, C. P. et al. Uniparental disomy at chromosome 11p15.5 followed by HRAS mutations in embryonal rhabdomyosarcoma: lessons from Costello syndrome. Hum. Mol. Genet. 16, 374–379 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Kratz, C. P. et al. Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes. Br. J. Cancer 12, 1392–1397 (2015).

    Article  Google Scholar 

  36. Hettmer, S. et al. Sarcomas induced in discrete subsets of prospectively isolated skeletal muscle cells. Proc. Natl Acad. Sci. USA 108, 20002–20007 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Linardic, C. M. et al. The PAX3–FKHR fusion gene of rhabdomyosarcoma cooperates with loss of p16INK4A to promote bypass of cellular senescence. Cancer Res. 67, 6691–6699 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Naini, S. et al. Defining the cooperative genetic changes that temporally drive alveolar rhabdomyosarcoma. Cancer Res. 68, 9583–9588 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Williamson, D. et al. Relationship between MYCN copy number and expression in rhabdomyosarcomas and correlation with adverse prognosis in the alveolar subtype. J. Clin. Oncol. 23, 880–888 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Kelly, K. M., Womer, R. B., Sorensen, P. H., Xiong, Q. B. & Barr, F. G. Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma. J. Clin. Oncol. 15, 1831–1836 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Skapek, S. X. et al. PAX–FOXO1 fusion status drives unfavorable outcome for children with rhabdomyosarcoma: a children's oncology group report. Pediatr. Blood Cancer 60, 1411–1417 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Anderson, M. J., Shelton, G. D., Cavenee, W. K. & Arden, K. C. Embryonic expression of the tumor-associated PAX3–FKHR fusion protein interferes with the developmental functions of Pax3. Proc. Natl Acad. Sci. USA 98, 1589–1594 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lagutina, I., Conway, S. J., Sublett, J. & Grosveld, G. C. Pax3–FKHR knock-in mice show developmental aberrations but do not develop tumors. Mol. Cell. Biol. 22, 7204–7216 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Relaix, F. et al. The transcriptional activator PAX3–FKHR rescues the defects of Pax3 mutant mice but induces a myogenic gain-of-function phenotype with ligand-independent activation of Met signaling in vivo. Genes Dev. 17, 2950–2965 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Barr, F. G. Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma. Oncogene 20, 5736–5746 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Keller, C. et al. Alveolar rhabdomyosarcomas in conditional Pax3:Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function. Genes Dev. 18, 2614–2626 (2004). This paper was the first to report a tumorigenic genetically engineered PAX3–FOXO1 (ARMS) mouse model. Tumorigenesis occurs from PAX3–FOXO1-expressing differentiating myofibres and is enhanced by Trp53 or Cdkn2a loss-of-function mutations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nishijo, K. et al. Credentialing a preclinical mouse model of alveolar rhabdomyosarcoma. Cancer Res. 69, 2902–2911 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Abraham, J. et al. Evasion mechanisms to Igf1r inhibition in rhabdomyosarcoma. Mol. Cancer Ther. 10, 697–707 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hosoyama, T. et al. IL-4R drives dedifferentiation, mitogenesis, and metastasis in rhabdomyosarcoma. Clin. Cancer Res. 17, 2757–2766 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kikuchi, K. et al. Cell-cycle dependent expression of a translocation-mediated fusion oncogene mediates checkpoint adaptation in rhabdomyosarcoma. PLoS Genet. 10, e1004107 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Abraham, J. et al. Lineage of origin in rhabdomyosarcoma informs pharmacological response. Genes Dev. 28, 1578–1591 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Coffin, C. M., Davis, J. L. & Borinstein, S. C. Syndrome-associated soft tissue tumours. Histopathology 64, 68–87 (2014).

    Article  PubMed  Google Scholar 

  53. Estep, A. L., Tidyman, W. E., Teitell, M. A., Cotter, P. D. & Rauen, K. A. HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy. Am. J. Med. Genet. A 140A, 8–16 (2006).

    Article  CAS  Google Scholar 

  54. Johnson, R. L. et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272, 1668–1671 (1996).

    Article  CAS  PubMed  Google Scholar 

  55. Li, F. P. & Fraumeni, J. F. Jr. Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J. Natl Cancer Inst. 43, 1365–1373 (1969).

    CAS  PubMed  Google Scholar 

  56. Ognjanovic, S., Olivier, M., Bergemann, T. L. & Hainaut, P. Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database. Cancer 118, 1387–1396 (2012).

    Article  CAS  PubMed  Google Scholar 

  57. Diller, L., Sexsmith, E., Gottlieb, A., Li, F. P. & Malkin, D. Germline p53 mutations are frequently detected in young children with rhabdomyosarcoma. J. Clin. Invest. 95, 1606–1611 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Jacks, T. et al. Tumor spectrum analysis in p53-mutant mice. Curr. Biol. 4, 1–7 (1994).

    Article  CAS  PubMed  Google Scholar 

  59. Taylor, A. C. et al. P53 mutation and MDM2 amplification frequency in pediatric rhabdomyosarcoma tumors and cell lines. Med. Pediatr. Oncol. 35, 96–103 (2000).

    Article  CAS  PubMed  Google Scholar 

  60. Keleti, J., Quezado, M. M., Abaza, M. M., Raffeld, M. & Tsokos, M. The MDM2 oncoprotein is overexpressed in rhabdomyosarcoma cell lines and stabilizes wild-type p53 protein. Am. J. Pathol. 149, 143–151 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Fleischmann, A., Jochum, W., Eferl, R., Witowsky, J. & Wagner, E. F. Rhabdomyosarcoma development in mice lacking Trp53 and Fos: tumor suppression by the Fos protooncogene. Cancer Cell 4, 477–482 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Nanni, P. et al. Development of rhabdomyosarcoma in HER-2/neu transgenic p53 mutant mice. Cancer Res. 63, 2728–2732 (2003).

    CAS  PubMed  Google Scholar 

  63. McMahon, A. P., Ingham, P. W. & Tabin, C. J. Developmental roles and clinical significance of hedgehog signaling. Curr. Top. Dev. Biol. 53, 1–114 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Gorlin, R. J. Nevoid basal cell carcinoma syndrome. Dermatol. Clin. 13, 113–125 (1995).

    Article  CAS  PubMed  Google Scholar 

  65. Hahn, H. et al. Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome. Nat. Med. 4, 619–622 (1998).

    Article  CAS  PubMed  Google Scholar 

  66. Bridge, J. A. 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 27, 337–344 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. Ragazzini, P. et al. Amplification of CDK4, MDM2, SAS and GLI genes in leiomyosarcoma, alveolar and embryonal rhabdomyosarcoma. Histol. Histopathol. 19, 401–411 (2004).

    CAS  PubMed  Google Scholar 

  68. Pressey, J. G., Anderson, J. R., Crossman, D. K., Lynch, J. C. & Barr, F. G. Hedgehog pathway activity in pediatric embryonal rhabdomyosarcoma and undifferentiated sarcoma: a report from the Children's Oncology Group. Pediatr. Blood Cancer 57, 930–938 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Zibat, A. et al. Activation of the hedgehog pathway confers a poor prognosis in embryonal and fusion gene-negative alveolar rhabdomyosarcoma. Oncogene 29, 6323–6330 (2010).

    Article  CAS  PubMed  Google Scholar 

  70. Corcoran, R. B. & Scott, M. P. A mouse model for medulloblastoma and basal cell nevus syndrome. J. Neurooncol. 53, 307–318 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Hahn, H. et al. Patched target Igf2 is indispensable for the formation of medulloblastoma and rhabdomyosarcoma. J. Biol. Chem. 275, 28341–28344 (2000).

    Article  CAS  PubMed  Google Scholar 

  72. Tostar, U. et al. Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development. J. Pathol. 208, 17–25 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Lee, Y. et al. Loss of suppressor-of-fused function promotes tumorigenesis. Oncogene 26, 6442–6447 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Mao, J. et al. A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway. Cancer Res. 66, 10171–10178 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hettmer, S. et al. Mutations in Hedgehog pathway genes in fetal rhabdomyomas. J. Pathol. 231, 44–52 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Niwa, H., Yamamura, K. & Miyazaki, J. Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108, 193–199 (1991).

    Article  CAS  PubMed  Google Scholar 

  77. Epstein, J. A., Shapiro, D. N., Cheng, J., Lam, P. Y. & Maas, R. L. Pax3 modulates expression of the c-Met receptor during limb muscle development. Proc. Natl Acad. Sci. USA 93, 4213–4218 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Trusolino, L. & Comoglio, P. M. Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat. Rev. Cancer 2, 289–300 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Sharp, R. et al. Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis. Nat. Med. 8, 1276–1280 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Tatsumi, R., Anderson, J. E., Nevoret, C. J., Halevy, O. & Allen, R. E. HGF/SF is present in normal adult skeletal muscle and is capable of activating satellite cells. Dev. Biol. 194, 114–128 (1998).

    Article  CAS  PubMed  Google Scholar 

  81. Meadors, J. L. et al. Murine rhabdomyosarcoma is immunogenic and responsive to T-cell-based immunotherapy. Pediatr. Blood Cancer 57, 921–929 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Yu, Y. et al. Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators. Nat. Med. 10, 175–181 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Carneiro, A. et al. Ezrin expression predicts local recurrence and development of metastases in soft tissue sarcomas. J. Clin. Pathol. 64, 689–694 (2011).

    Article  PubMed  Google Scholar 

  84. Yu, Y., Davicioni, E., Triche, T. J. & Merlino, G. The homeoprotein six1 transcriptionally activates multiple protumorigenic genes but requires ezrin to promote metastasis. Cancer Res. 66, 1982–1989 (2006).

    Article  CAS  PubMed  Google Scholar 

  85. Yu, Y. et al. Epigenetic drugs can stimulate metastasis through enhanced expression of the pro-metastatic Ezrin gene. PLoS ONE 5, e12710 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Bolden, J. E., Peart, M. J. & Johnstone, R. W. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov. 5, 769–784 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Rossbach, H. C., Lacson, A., Grana, N. H. & Barbosa, J. L. Duchenne muscular dystrophy and concomitant metastatic alveolar rhabdomyosarcoma. J. Pediatr. Hematol. Oncol. 21, 528–530 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. Jakab, Z., Szegedi, I., Balogh, E., Kiss, C. & Olah, E. Duchenne muscular dystrophy-rhabdomyosarcoma, ichthyosis vulgaris/acute monoblastic leukemia: association of rare genetic disorders and childhood malignant diseases. Med. Pediatr. Oncol. 39, 66–68 (2002).

    Article  PubMed  Google Scholar 

  89. Fanzani, A., Monti, E., Donato, R. & Sorci, G. Muscular dystrophies share pathogenetic mechanisms with muscle sarcomas. Trends Mol. Med. 19, 546–554 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. Chamberlain, J. S., Metzger, J., Reyes, M., Townsend, D. & Faulkner, J. A. Dystrophin-deficient mdx mice display a reduced life span and are susceptible to spontaneous rhabdomyosarcoma. FASEB J. 21, 2195–2204 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Fernandez, K., Serinagaoglu, Y., Hammond, S., Martin, L. T. & Martin, P. T. Mice lacking dystrophin or α sarcoglycan spontaneously develop embryonal rhabdomyosarcoma with cancer-associated p53 mutations and alternatively spliced or mutant Mdm2 transcripts. Am. J. Pathol. 176, 416–434 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Schmidt, W. M. et al. DNA damage, somatic aneuploidy, and malignant sarcoma susceptibility in muscular dystrophies. PLoS Genet. 7, e1002042 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Sher, R. B., Cox, G. A., Mills, K. D. & Sundberg, J. P. Rhabdomyosarcomas in aging A/J mice. PLoS ONE 6, e23498 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Hosur, V. et al. Dystrophin and dysferlin double mutant mice: a novel model for rhabdomyosarcoma. Cancer Genet. 205, 232–241 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Wang, Y. et al. Dystrophin is a tumor suppressor in human cancers with myogenic programs. Nat. Genet. 46, 601–606 (2014). This paper shows that intragenic deletion of the MD-associated DMD gene is a common mechanism by which myogenic lineage tumours progress to high-grade sarcomas, including ERMS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. White, R., Rose, K. & Zon, L. Zebrafish cancer: the state of the art and the path forward. Nat. Rev. Cancer 13, 624–636 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Srinivas, B. P., Woo, J., Leong, W. Y. & Roy, S. A conserved molecular pathway mediates myoblast fusion in insects and vertebrates. Nat. Genet. 39, 781–786 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Langenau, D. M. et al. Effects of RAS on the genesis of embryonal rhabdomyosarcoma. Genes Dev. 21, 1382–1395 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Ignatius, M. S. et al. In vivo imaging of tumor-propagating cells, regional tumor heterogeneity, and dynamic cell movements in embryonal rhabdomyosarcoma. Cancer Cell 21, 680–693 (2012). References 98 and 99 describe the first zebrafish model for ERMS, which is RAS-induced, and these ERMS tumours are composed of a heterogeneous population of cells with differing growth versus metastatic properties.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Doyle, B. et al. p53 mutation and loss have different effects on tumourigenesis in a novel mouse model of pleomorphic rhabdomyosarcoma. J. Pathol. 222, 129–137 (2010).

    Article  CAS  PubMed  Google Scholar 

  101. Gonzalez, C. Drosophila melanogaster: a model and a tool to investigate malignancy and identify new therapeutics. Nat. Rev. Cancer 13, 172–183 (2013).

    Article  CAS  PubMed  Google Scholar 

  102. Xue, L., Li, X. & Noll, M. Multiple protein functions of paired in Drosophila development and their conservation in the Gooseberry and Pax3 homologs. Development 128, 395–405 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Xue, L. & Noll, M. The functional conservation of proteins in evolutionary alleles and the dominant role of enhancers in evolution. EMBO J. 15, 3722–3731 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Brand, A. H. & Perrimon, N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118, 401–415 (1993).

    Article  CAS  PubMed  Google Scholar 

  105. Galindo, R. L., Allport, J. A. & Olson, E. N. A. Drosophila model of the rhabdomyosarcoma initiator PAX7–FKHR. Proc. Natl Acad. Sci. USA 103, 13439–13444 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Avirneni-Vadlamudi, U. et al. Drosophila and mammalian models uncover a role for the myoblast fusion gene TANC1 in rhabdomyosarcoma. J. Clin. Invest. 122, 403–407 (2012). References 105 and 106 describe the generation and characterization of the Drosophila PAX7–FOXO1 model, and uncover misregulated myoblast fusion signalling as a mechanism of ARMS pathogenesis.

    Article  CAS  PubMed  Google Scholar 

  107. Rau, A. et al. rolling pebbles (rols) is required in Drosophila muscle precursors for recruitment of myoblasts for fusion. Development 128, 5061–5073 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. Menon, S. D. & Chia, W. Drosophila rolling pebbles: a multidomain protein required for myoblast fusion that recruits D-Titin in response to the myoblast attractant Dumbfounded. Dev. Cell 1, 691–703 (2001).

    Article  CAS  PubMed  Google Scholar 

  109. Chen, E. H. & Olson, E. N. Antisocial, an intracellular adaptor protein, is required for myoblast fusion in Drosophila. Dev. Cell 1, 705–715 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. Crose, L. E. et al. Alveolar rhabdomyosarcoma-associated PAX3–FOXO1 promotes tumorigenesis via Hippo pathway suppression. J. Clin. Invest. 124, 285–296 (2014).

    Article  CAS  PubMed  Google Scholar 

  111. Tremblay, A. M. et al. The Hippo transducer YAP1 transforms activated satellite cells and is a potent effector of embryonal rhabdomyosarcoma formation. Cancer Cell 26, 273–287 (2014). References 110 and 111 report Hippo pathway misregulation in ARMS and ERMS.

    Article  CAS  PubMed  Google Scholar 

  112. Liu-Chittenden, Y. et al. Genetic and pharmacological disruption of the TEAD–YAP complex suppresses the oncogenic activity of YAP. Genes Dev. 26, 1300–1305 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Zhou, Z. et al. Targeting Hippo pathway by specific interruption of YAP–TEAD interaction using cyclic YAP-like peptides. FASEB J. 29, 724–732 (2015).

    Article  CAS  PubMed  Google Scholar 

  114. Spunt, S. L. et al. Aggressive surgery is unwarranted for biliary tract rhabdomyosarcoma. J. Pediatr. Surg. 35, 309–316 (2000).

    Article  CAS  PubMed  Google Scholar 

  115. Heyn, R. et al. Preservation of the bladder in patients with rhabdomyosarcoma. J. Clin. Oncol. 15, 69–75 (1997).

    Article  CAS  PubMed  Google Scholar 

  116. Lisboa, S. et al. Genetic diagnosis of alveolar rhabdomyosarcoma in the bone marrow of a patient without evidence of primary tumor. Pediatr. Blood Cancer 51, 554–557 (2008).

    Article  PubMed  Google Scholar 

  117. Shinkoda, Y., Nagatoshi, Y., Fukano, R., Nishiyama, K. & Okamura, J. Rhabdomyosarcoma masquerading as acute leukemia. Pediatr. Blood Cancer 52, 286–287 (2009).

    Article  PubMed  Google Scholar 

  118. Srinivas, U. et al. A case of rhabdomyosarcoma masquerading as acute leukemia at presentation: a case report. Indian J. Pathol. Microbiol. 50, 917–919 (2007).

    PubMed  Google Scholar 

  119. Storer, N. Y. et al. Zebrafish rhabdomyosarcoma reflects the developmental stage of oncogene expression during myogenesis. Development 140, 3040–3050 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Heerema-McKenney, A. et al. Diffuse myogenin expression by immunohistochemistry is an independent marker of poor survival in pediatric rhabdomyosarcoma: a tissue microarray study of 71 primary tumors including correlation with molecular phenotype. Am. J. Surg. Pathol. 32, 1513–1522 (2008).

    Article  PubMed  Google Scholar 

  121. Rubin, B. P. et al. Evidence for an unanticipated relationship between undifferentiated pleomorphic sarcoma and embryonal rhabdomyosarcoma. Cancer Cell 19, 177–191 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Brown, C. B., Engleka, K. A., Wenning, J., Min Lu, M. & Epstein, J. A. Identification of a hypaxial somite enhancer element regulating Pax3 expression in migrating myoblasts and characterization of hypaxial muscle Cre transgenic mice. Genesis 41, 202–209 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Blum, J. M. et al. Distinct and overlapping sarcoma subtypes initiated from muscle stem and progenitor cells. Cell Rep. 5, 933–940 (2013). References 121 and 123 illustrate that the cell of origin influences which subtype of RMS or UPS can arise, and that RMS and UPS lie in a previously unrecognized continuum.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Hatley, M. E. et al. A mouse model of rhabdomyosarcoma originating from the adipocyte lineage. Cancer Cell 22, 536–546 (2012). This paper explains that constitutive SHH signalling via dominantly activated SMO drives ERMS in adipocyte progenitors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Tang, W. et al. White fat progenitor cells reside in the adipose vasculature. Science 322, 583–586 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Lee, K. Y. et al. Lessons on conditional gene targeting in mouse adipose tissue. Diabetes 62, 864–874 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Rajurkar, M. et al. Distinct cellular origin and genetic requirement of Hedgehog–Gli in postnatal rhabdomyosarcoma genesis. Oncogene 33, 5370–5378 (2014).

    Article  CAS  PubMed  Google Scholar 

  128. Weigel, B. et al. Phase 2 trial of cixutumumab in children, adolescents, and young adults with refractory solid tumors: a report from the Children's Oncology Group. Pediatr. Blood Cancer 61, 452–456 (2014).

    Article  CAS  PubMed  Google Scholar 

  129. Huang, F. et al. Differential mechanisms of acquired resistance to insulin-like growth factor-i receptor antibody therapy or to a small-molecule inhibitor, BMS-754807, in a human rhabdomyosarcoma model. Cancer Res. 70, 7221–7231 (2010).

    Article  CAS  PubMed  Google Scholar 

  130. Pappo, A. S. et al. Survival after relapse in children and adolescents with rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study Group. J. Clin. Oncol. 17, 3487–3493 (1999).

    Article  CAS  PubMed  Google Scholar 

  131. Geoerger, B. et al. Phase II trial of temsirolimus in children with high-grade glioma, neuroblastoma and rhabdomyosarcoma. Eur. J. Cancer 48, 253–262 (2012).

    Article  CAS  PubMed  Google Scholar 

  132. Aslam, M. I. et al. Dynamic and nuclear expression of PDGFRα and IGF-1R in alveolar rhabdomyosarcoma. Mol. Cancer Res. 11, 1303–1313 (2013).

    Article  CAS  PubMed  Google Scholar 

  133. Horsley, V., Jansen, K. M., Mills, S. T. & Pavlath, G. K. IL-4 acts as a myoblast recruitment factor during mammalian muscle growth. Cell 113, 483–494 (2003).

    Article  CAS  PubMed  Google Scholar 

  134. Thalhammer, V. et al. PLK1 phosphorylates PAX3–FOXO1, the inhibition of which triggers regression of alveolar rhabdomyosarcoma. Cancer Res. 75, 98–110 (2015).

    Article  CAS  PubMed  Google Scholar 

  135. Albacker, C. E. et al. The histone methyltransferase SUV39H1 suppresses embryonal rhabdomyosarcoma formation in zebrafish. PLoS ONE 8, e64969 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Le, X. et al. A novel chemical screening strategy in zebrafish identifies common pathways in embryogenesis and rhabdomyosarcoma development. Development 140, 2354–2364 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Chen, E. Y. et al. Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma. Proc. Natl Acad. Sci. USA 111, 5349–5354 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Wang, H. et al. IFN-β production by TLR4-stimulated innate immune cells is negatively regulated by GSK3-β. J. Immunol. 181, 6797–6802 (2008).

    Article  CAS  PubMed  Google Scholar 

  139. Patel, S. & Woodgett, J. Glycogen synthase kinase-3 and cancer: good cop, bad cop? Cancer Cell 14, 351–353 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Kremer, A., Louis, J. V., Jaworski, T. & Van Leuven, F. GSK3 and Alzheimer's disease: facts and fiction. Front. Mol. Neurosci. 4, 17 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Renshaw, J. et al. Dual blockade of the PI3K/AKT/mTOR (AZD8055) and RAS/MEK/ERK (AZD6244) pathways synergistically inhibits rhabdomyosarcoma cell growth in vitro and in vivo. Clin. Cancer Res. 19, 5940–5951 (2013).

    Article  CAS  PubMed  Google Scholar 

  142. Graab, U., Hahn, H. & Fulda, S. Identification of a novel synthetic lethality of combined inhibition of hedgehog and PI3K signaling in rhabdomyosarcoma. Oncotarget 6, 8722–8735 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Lagutina, I. V. et al. Modeling of the human alveolar rhabdomyosarcoma Pax3–Foxo1 chromosome translocation in mouse myoblasts using CRISPR–Cas9 nuclease. PLoS Genet. 11, e1004951 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Tentler, J. J. et al. Patient-derived tumour xenografts as models for oncology drug development. Nat. Rev. Clin. Oncol. 9, 338–350 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Siolas, D. & Hannon, G. J. Patient-derived tumor xenografts: transforming clinical samples into mouse models. Cancer Res. 73, 5315–5319 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Monsma, D. J. et al. Using a rhabdomyosarcoma patient-derived xenograft to examine precision medicine approaches and model acquired resistance. Pediatr. Blood Cancer 61, 1570–1577 (2014).

    Article  CAS  PubMed  Google Scholar 

  147. Stebbing, J. et al. Patient-derived xenografts for individualized care in advanced sarcoma. Cancer 120, 2006–2015 (2014).

    Article  PubMed  Google Scholar 

  148. Collins, F. S. & Varmus, H. A new initiative on precision medicine. N. Engl. J. Med. 372, 793–795 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Abmayr, S. M. & Pavlath, G. K. Myoblast fusion: lessons from flies and mice. Development 139, 641–656 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Bour, B. A., Chakravarti, M., West, J. M. & Abmayr, S. M. Drosophila SNS, a member of the immunoglobulin superfamily that is essential for myoblast fusion. Genes Dev. 14, 1498–1511 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Strunkelnberg, M. et al. rst and its paralogue kirre act redundantly during embryonic muscle development in Drosophila. Development 128, 4229–4239 (2001).

    Article  CAS  PubMed  Google Scholar 

  152. Ruiz-Gomez, M., Coutts, N., Price, A., Taylor, M. V. & Bate, M. Drosophila dumbfounded: a myoblast attractant essential for fusion. Cell 102, 189–198 (2000).

    Article  CAS  PubMed  Google Scholar 

  153. Onel, S., Bolke, L. & Klambt, C. The Drosophila ARF6–GEF Schizo controls commissure formation by regulating Slit. Development 131, 2587–2594 (2004).

    Article  PubMed  CAS  Google Scholar 

  154. Hindi, S. M., Tajrishi, M. M. & Kumar, A. Signaling mechanisms in mammalian myoblast fusion. Sci. Signal. 6, re2 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Sohn, R. L. et al. A role for nephrin, a renal protein, in vertebrate skeletal muscle cell fusion. Proc. Natl Acad. Sci. USA 106, 9274–9279 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Millay, D. P. et al. Myomaker is a membrane activator of myoblast fusion and muscle formation. Nature 499, 301–305 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Millay, D. P. & Olson, E. N. Making muscle or mitochondria by selective splicing of PGC-1α. Cell. Metab. 17, 3–4 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We apologize to the many authors who have done important work on rhabdomyosarcoma (RMS) that we were unable to cite owing to space constraints. This work was supported in part by grants from the US National Cancer Institute (K08CA151649) and American Lebanese Syrian Associated Charities (to M.E.H.), the American Cancer Society Research Scholars Award (to R.L.G.), the Burroughs Wellcome Fund Career Award for Medical Scientists (to R.L.G.), and the Alex's Lemonade Stand Foundation “A” Award (to R.L.G.). The pleomorphic RMS image was kindly provided by P. Kapur.

Author information

Authors and Affiliations

  1. Department of Pathology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, 75390–9072, Texas, USA

    Venkatesh P. Kashi & Rene L. Galindo

  2. Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, 38105, Tennessee, USA

    Mark E. Hatley

  3. Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, 75390–9148, Texas, USA

    Rene L. Galindo

  4. Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, 75390–9063, Texas, USA

    Rene L. Galindo

Authors
  1. Venkatesh P. Kashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark E. Hatley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rene L. Galindo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Mark E. Hatley or Rene L. Galindo.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Satellite cells

Stem-like cells that reside within muscle fibres and are involved in skeletal muscle growth and repair.

Undifferentiated pleomorphic sarcoma

(UPS). A soft tissue sarcoma possessing pleomorphic cellular and nuclear features, and with no identifiable line of cytodifferentiation.

Myoblasts

Precursor cells that differentiate, fuse, and form syncytial muscle. Myoblasts are present throughout life, and include embryonic, fetal and postnatal populations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kashi, V., Hatley, M. & Galindo, R. Probing for a deeper understanding of rhabdomyosarcoma: insights from complementary model systems. Nat Rev Cancer 15, 426–439 (2015). https://doi.org/10.1038/nrc3961

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3961

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer