Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis

Richard Sharp; Juan A. Recio; Chamelli Jhappan; Toshiyuki Otsuka; Shiquan Liu; Yanlin Yu; Wenjing Liu; Miriam Anver; Fariba Navid; Lee J. Helman; Ronald A. DePinho; Glenn Merlino

doi:10.1038/nm787

Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis

Richard Sharp, Juan A. Recio, Chamelli Jhappan, Toshiyuki Otsuka, Shiquan Liu, Yanlin Yu, Wenjing Liu, Miriam Anver, Fariba Navid, Lee J. Helman, Ronald A. DePinho, Glenn Merlino

Quantitative Health Sciences

Research output: Contribution to journal › Article › peer-review

129 Scopus citations

Abstract

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, yet molecular events associated with the genesis and progression of this potentially fatal disease are largely unknown. For the molecules and pathways that have been implicated, genetic validation has been impeded by lack of a mouse model of RMS. Here we show that simultaneous loss of Ink4a/Arf function and disruption of c-Met signaling in Ink4a/Arf^-/- mice transgenic for hepatocyte growth factor/scatter factor (HGF/SF) induces RMS with extremely high penetrance and short latency. In cultured myoblasts, c-Met activation and Ink4a/Arf loss suppress myogenesis in an additive fashion. Our data indicate that human c-MET and INK40/ARF, situated at the nexus of pathways regulating myogenic growth and differentiation, represent critical targets in RMS pathogenesis. The marked synergism in mice between aberrant c-Met signaling and Ink4a/Arf inactivation, lesions individually implicated in human RMS, suggests a therapeutic combination to combat this devastating childhood cancer.

Original language	English (US)
Pages (from-to)	1276-1280
Number of pages	5
Journal	Nature Medicine
Volume	8
Issue number	11
DOIs	https://doi.org/10.1038/nm787
State	Published - Nov 1 2002

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1038/nm787

Cite this

@article{04d7e755d2494b22948d0983c9d20bec,

title = "Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis",

abstract = "Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, yet molecular events associated with the genesis and progression of this potentially fatal disease are largely unknown. For the molecules and pathways that have been implicated, genetic validation has been impeded by lack of a mouse model of RMS. Here we show that simultaneous loss of Ink4a/Arf function and disruption of c-Met signaling in Ink4a/Arf-/- mice transgenic for hepatocyte growth factor/scatter factor (HGF/SF) induces RMS with extremely high penetrance and short latency. In cultured myoblasts, c-Met activation and Ink4a/Arf loss suppress myogenesis in an additive fashion. Our data indicate that human c-MET and INK40/ARF, situated at the nexus of pathways regulating myogenic growth and differentiation, represent critical targets in RMS pathogenesis. The marked synergism in mice between aberrant c-Met signaling and Ink4a/Arf inactivation, lesions individually implicated in human RMS, suggests a therapeutic combination to combat this devastating childhood cancer.",

author = "Richard Sharp and Recio, {Juan A.} and Chamelli Jhappan and Toshiyuki Otsuka and Shiquan Liu and Yanlin Yu and Wenjing Liu and Miriam Anver and Fariba Navid and Helman, {Lee J.} and DePinho, {Ronald A.} and Glenn Merlino",

note = "Funding Information: Acknowledgments We thank D. Spicer, H. Takayama, G. Celli, K. Miura, P. Meltzer, L. Wakefield, G.Vande Woude and J. Ward for useful discussions; M. Tsokos for assistance with initial histopathological evaluation; J. Owens for electron microscopy; H. Wimbrow for animal colony husbandry; and B. Kasprzak and D. Butcher for immunohistochemistry. We thank the following for plasmid DNAs: G. Bell (for mouse IGF-II); B. Vogelstein (for human MDM2); Ed Harlow (for human CDK4); K. Huppi (for mouse GAPDH); E.Olson (for mouse myoD and myogenin); P. Seale (for pax7); and C. Ponzetto (for mouse myf5). This work was supported, in part, by the Cooperative Human Tissue Network, which is funded by the National Cancer Institute, and in part by NIH U01CA84313-04. R.A.D. is an American Cancer Society Research Professor.",

year = "2002",

month = nov,

day = "1",

doi = "10.1038/nm787",

language = "English (US)",

volume = "8",

pages = "1276--1280",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "11",

}

TY - JOUR

T1 - Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis

AU - Sharp, Richard

AU - Recio, Juan A.

AU - Jhappan, Chamelli

AU - Otsuka, Toshiyuki

AU - Liu, Shiquan

AU - Yu, Yanlin

AU - Liu, Wenjing

AU - Anver, Miriam

AU - Navid, Fariba

AU - Helman, Lee J.

AU - DePinho, Ronald A.

AU - Merlino, Glenn

N1 - Funding Information: Acknowledgments We thank D. Spicer, H. Takayama, G. Celli, K. Miura, P. Meltzer, L. Wakefield, G.Vande Woude and J. Ward for useful discussions; M. Tsokos for assistance with initial histopathological evaluation; J. Owens for electron microscopy; H. Wimbrow for animal colony husbandry; and B. Kasprzak and D. Butcher for immunohistochemistry. We thank the following for plasmid DNAs: G. Bell (for mouse IGF-II); B. Vogelstein (for human MDM2); Ed Harlow (for human CDK4); K. Huppi (for mouse GAPDH); E.Olson (for mouse myoD and myogenin); P. Seale (for pax7); and C. Ponzetto (for mouse myf5). This work was supported, in part, by the Cooperative Human Tissue Network, which is funded by the National Cancer Institute, and in part by NIH U01CA84313-04. R.A.D. is an American Cancer Society Research Professor.

PY - 2002/11/1

Y1 - 2002/11/1

N2 - Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, yet molecular events associated with the genesis and progression of this potentially fatal disease are largely unknown. For the molecules and pathways that have been implicated, genetic validation has been impeded by lack of a mouse model of RMS. Here we show that simultaneous loss of Ink4a/Arf function and disruption of c-Met signaling in Ink4a/Arf-/- mice transgenic for hepatocyte growth factor/scatter factor (HGF/SF) induces RMS with extremely high penetrance and short latency. In cultured myoblasts, c-Met activation and Ink4a/Arf loss suppress myogenesis in an additive fashion. Our data indicate that human c-MET and INK40/ARF, situated at the nexus of pathways regulating myogenic growth and differentiation, represent critical targets in RMS pathogenesis. The marked synergism in mice between aberrant c-Met signaling and Ink4a/Arf inactivation, lesions individually implicated in human RMS, suggests a therapeutic combination to combat this devastating childhood cancer.

AB - Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, yet molecular events associated with the genesis and progression of this potentially fatal disease are largely unknown. For the molecules and pathways that have been implicated, genetic validation has been impeded by lack of a mouse model of RMS. Here we show that simultaneous loss of Ink4a/Arf function and disruption of c-Met signaling in Ink4a/Arf-/- mice transgenic for hepatocyte growth factor/scatter factor (HGF/SF) induces RMS with extremely high penetrance and short latency. In cultured myoblasts, c-Met activation and Ink4a/Arf loss suppress myogenesis in an additive fashion. Our data indicate that human c-MET and INK40/ARF, situated at the nexus of pathways regulating myogenic growth and differentiation, represent critical targets in RMS pathogenesis. The marked synergism in mice between aberrant c-Met signaling and Ink4a/Arf inactivation, lesions individually implicated in human RMS, suggests a therapeutic combination to combat this devastating childhood cancer.

UR - http://www.scopus.com/inward/record.url?scp=0036851869&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036851869&partnerID=8YFLogxK

U2 - 10.1038/nm787

DO - 10.1038/nm787

M3 - Article

C2 - 12368906

AN - SCOPUS:0036851869

SN - 1078-8956

VL - 8

SP - 1276

EP - 1280

JO - Nature Medicine

JF - Nature Medicine

IS - 11

ER -

Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this