title: Hedgehog-driven myogenic tumors recapitulate skeletal muscle cellular heterogeneity.
abstract: Hedgehog (Hh) pathway activation in R26-SmoM2;CAGGS-CreER mice, which carry a tamoxifen-inducible activated Smoothened allele (SmoM2), results in numerous microscopic tumor foci in mouse skeletal muscle. These tumors exhibit a highly differentiated myogenic phenotype and resemble human fetal rhabdomyomas. This study sought to apply previously established strategies to isolate lineally distinct populations of normal mouse myofiber-associated cells in order to examine cellular heterogeneity in SmoM2 tumors. We demonstrate that established SmoM2 tumors are composed of cells expressing myogenic, adipocytic and hematopoietic lineage markers and differentiation capacity. SmoM2 tumors thus recapitulate the phenotypic and functional hetereogeneity observed in normal mouse skeletal muscle. SmoM2 tumors also contain an expanded population of PAX7+ and MyoD+ satellite-like cells with extremely low clonogenic activity. Selective activation of Hh signaling in freshly isolated muscle satellite cells enhanced terminal myogenic differentiation without stimulating proliferation. Our findings support the conclusion that SmoM2 tumors represent an aberrant skeletal muscle state and demonstrate that, similar to normal muscle, myogenic tumors contain functionally distinct cell subsets, including cells lacking myogenic differentiation potential.
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA; Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Germany. Electronic address: simone.hettmer@uniklinik-freiburg.de.
authors.forename: Simone
authors.initials: S
authors.lastname: Hettmer
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lin
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA.
authors.forename: Daria
authors.initials: D
authors.lastname: Tchessalova
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Tortorici
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Castiglioni
authors.affiliation: Department of Medicine, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Tushar
authors.initials: T
authors.lastname: Desai
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Junhao
authors.initials: J
authors.lastname: Mao
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McMahon
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
mesh_terms: D000483:Alleles; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D005434:Flow Cytometry; D053823:Hedgehog Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology*; D009379:Neoplasms, Muscle Tissue / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype
chemical_list: D053823:Hedgehog Proteins
keywords: Differentiation; Hedgehog signaling; Intratumoral cellular heterogeneity; Skeletal muscle