2. Academic Validation
  3. Single-cell profiling of alveolar rhabdomyosarcoma reveals RAS pathway inhibitors as cell-fate hijackers with therapeutic relevance

Single-cell profiling of alveolar rhabdomyosarcoma reveals RAS pathway inhibitors as cell-fate hijackers with therapeutic relevance

  • Sci Adv. 2023 Feb 10;9(6):eade9238. doi: 10.1126/sciadv.ade9238.
Sara G Danielli 1,  Ermelinda Porpiglia 2 3,  Andrea J De Micheli 1,  Natalia Navarro 4,  Michael J Zellinger 5,  Ingrid Bechtold 1,  Samanta Kisele 1,  Larissa Volken 1,  Joana G Marques 1,  Stephanie Kasper 1,  Peter K Bode 6,  Anton G Henssen 7,  Dennis Gürgen 8,  Olivier Delattre 9,  Didier Surdez 9 10,  Josep Roma 4,  Peter Bühlmann 5,  Helen M Blau 2,  Marco Wachtel 1,  Beat W Schäfer 1
Affiliations

Affiliations

  • 1 Department of Oncology and Children's Research Center, University Children's Hospital of Zurich, Zürich 8032, Switzerland.
  • 2 Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 3 Department of Biomedicine, Aarhus University, Aarhus C 8000, Denmark.
  • 4 Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain.
  • 5 Seminar for Statistics, ETH Zürich, Zürich 8092, Switzerland.
  • 6 Department of Pathology, University Hospital Zurich, Zurich, Switzerland.
  • 7 Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin 13353, Germany.
  • 8 EPO Experimental Pharmacology and Oncology Berlin-Buch GmbH Berlin 13125, Germany.
  • 9 INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Laboratory, PSL Research University, SIREDO Oncology Center, Institut Curie Research Center, Paris 75005, France.
  • 10 Balgrist University Hospital, Faculty of Medicine, University of Zurich (UZH), Zurich, Switzerland.
PMID: 36753540 DOI: 10.1126/sciadv.ade9238
Abstract

Rhabdomyosarcoma (RMS) is a group of pediatric cancers with features of developing skeletal muscle. The cellular hierarchy and mechanisms leading to developmental arrest remain elusive. Here, we combined single-cell RNA sequencing, mass cytometry, and high-content imaging to resolve intratumoral heterogeneity of patient-derived primary RMS cultures. We show that the aggressive alveolar RMS (aRMS) subtype contains plastic muscle stem-like cells and cycling progenitors that drive tumor growth, and a subpopulation of differentiated cells that lost its proliferative potential and correlates with better outcomes. While chemotherapy eliminates cycling progenitors, it enriches aRMS for muscle stem-like cells. We screened for drugs hijacking aRMS toward clinically favorable subpopulations and identified a combination of Raf and MEK inhibitors that potently induces myogenic differentiation and inhibits tumor growth. Overall, our work provides insights into the developmental states underlying aRMS aggressiveness, chemoresistance, and progression and identifies the Ras pathway as a promising therapeutic target.

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