title: Acute tissue injury activates satellite cells and promotes sarcoma formation via the HGF/c-MET signaling pathway.
abstract: Some patients with soft-tissue sarcoma (STS) report a history of injury at the site of their tumor. Although this phenomenon is widely reported, there are relatively few experimental systems that have directly assessed the role of injury in sarcoma formation. We recently described a mouse model of STS whereby p53 is deleted and oncogenic Kras is activated in muscle satellite cells via a Pax7(CreER) driver following intraperitoneal injection with tamoxifen. Here, we report that after systemic injection of tamoxifen, the vast majority of Pax7-expressing cells remain quiescent despite mutation of p53 and Kras. The fate of these muscle progenitors is dramatically altered by tissue injury, which leads to faster kinetics of sarcoma formation. In adult muscle, quiescent satellite cells will transition into an active state in response to hepatocyte growth factor (HGF). We show that modulating satellite cell quiescence via intramuscular injection of HGF increases the penetrance of sarcoma formation at the site of injection, which is dependent on its cognate receptor c-MET. Unexpectedly, the tumor-promoting effect of tissue injury also requires c-Met. These results reveal a mechanism by which HGF/c-MET signaling promotes tumor formation after tissue injury in a mouse model of primary STS, and they may explain why some patients develop a STS at the site of injury.
authors.affiliation: Department of Pediatrics, Division of Hematology-Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: David
authors.initials: D
authors.lastname: Van Mater
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Leonor
authors.initials: L
authors.lastname: Añó
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Jordan M
authors.initials: JM
authors.lastname: Blum
authors.affiliation: Department of Embryology, Carnegie Institution for Science, Baltimore, Maryland.
authors.forename: Micah T
authors.initials: MT
authors.lastname: Webster
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: WeiQiao
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Nerissa
authors.initials: N
authors.lastname: Williams
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Cardona
authors.affiliation: Department of Embryology, Carnegie Institution for Science, Baltimore, Maryland.
authors.forename: Chen-Ming
authors.initials: CM
authors.lastname: Fan
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina. Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina. david.kirsch@duke.edu.
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
mesh_terms: D000483:Alleles; D000818:Animals; D054715:Cardiotoxins / Q000378:metabolism; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000166:cytology*; D051763:PAX7 Transcription Factor / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D012509:Sarcoma / Q000378:metabolism*; D015398:Signal Transduction; D012983:Soft Tissue Neoplasms / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D054715:Cardiotoxins; C553307:HGF protein, mouse; D051763:PAX7 Transcription Factor; C497322:Pax7 protein, mouse; D016159:Tumor Suppressor Protein p53; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D018631:ras Proteins