title: Hepatocyte Growth Factor-mediated satellite cells niche perturbation promotes development of distinct sarcoma subtypes.
abstract: Embryonal Rhabdomyosarcoma (ERMS) and Undifferentiated Pleomorphic Sarcoma (UPS) are distinct sarcoma subtypes. Here we investigate the relevance of the satellite cell (SC) niche in sarcoma development by using Hepatocyte Growth Factor (HGF) to perturb the niche microenvironment. In a Pax7 wild type background, HGF stimulation mainly causes ERMS that originate from satellite cells following a process of multistep progression. Conversely, in a Pax7 null genotype ERMS incidence drops, while UPS becomes the most frequent subtype. Murine EfRMS display genetic heterogeneity similar to their human counterpart. Altogether, our data demonstrate that selective perturbation of the SC niche results in distinct sarcoma subtypes in a Pax7 lineage-dependent manner, and define a critical role for the Met axis in sarcoma initiation. Finally, our results provide a rationale for the use of combination therapy, tailored on specific amplifications and activated signaling pathways, to minimize resistance emerging from sarcomas heterogeneity.
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy.|CeRMS, Center for Experimental Research and Medical Studies, Turin, Italy.
authors.forename: Deborah
authors.initials: D
authors.lastname: Morena
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy.|CeRMS, Center for Experimental Research and Medical Studies, Turin, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Maestro
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy.|CeRMS, Center for Experimental Research and Medical Studies, Turin, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bersani
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy.|CeRMS, Center for Experimental Research and Medical Studies, Turin, Italy.
authors.forename: Paolo Emanuele
authors.initials: PE
authors.lastname: Forni
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy.|CeRMS, Center for Experimental Research and Medical Studies, Turin, Italy.
authors.forename: Marcello Francesco
authors.initials: MF
authors.lastname: Lingua
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy.|CeRMS, Center for Experimental Research and Medical Studies, Turin, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Foglizzo
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy.|CeRMS, Center for Experimental Research and Medical Studies, Turin, Italy.
authors.forename: Petar
authors.initials: P
authors.lastname: Šćepanović
authors.affiliation: Department of Veterinary Science, University of Turin, Grugliasco, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Miretti
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Morotti
authors.affiliation: Pediatric Oncology Branch, Oncogenomics Section, Center for Cancer Research, National Institutes of Health (NIH), Bethesda, United States.
authors.forename: Jack F
authors.initials: JF
authors.lastname: Shern
authors.affiliation: Pediatric Oncology Branch, Oncogenomics Section, Center for Cancer Research, National Institutes of Health (NIH), Bethesda, United States.
authors.forename: Javed
authors.initials: J
authors.lastname: Khan
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Ala
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Provero
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy.
authors.forename: Valentina
authors.identifier: http://orcid.org/0000-0002-2283-2807
authors.initials: V
authors.lastname: Sala
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Crepaldi
authors.affiliation: Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Gasparini
authors.affiliation: Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Casanova
authors.affiliation: Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ferrari
authors.affiliation: Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Sozzi
authors.affiliation: CeRMS, Center for Experimental Research and Medical Studies, Turin, Italy.|Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.|Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, United States.
authors.forename: Roberto
authors.initials: R
authors.lastname: Chiarle
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy.|CeRMS, Center for Experimental Research and Medical Studies, Turin, Italy.
authors.forename: Carola
authors.initials: C
authors.lastname: Ponzetto
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy.|CeRMS, Center for Experimental Research and Medical Studies, Turin, Italy.
authors.forename: Riccardo
authors.identifier: http://orcid.org/0000-0003-1277-6263
authors.initials: R
authors.lastname: Taulli
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D008822:Mice, Transgenic; D051763:PAX7 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012509:Sarcoma / Q000235:genetics / Q000473:pathology*
chemical_list: C066855:HGF protein, human; D051763:PAX7 Transcription Factor; D017228:Hepatocyte Growth Factor
keywords: HGF/met axis; cell biology; clonal evolution; combination therapy; developmental biology; embryonal rhabdomyosarcoma; human; mouse; stem cell niche; stem cells; undifferentiated pleomorphic sarcoma