2. Academic Validation
  3. PAX translocations remodel mitochondrial metabolism through altered leucine usage in rhabdomyosarcoma

PAX translocations remodel mitochondrial metabolism through altered leucine usage in rhabdomyosarcoma

  • Cell. 2025 May 15;188(10):2757-2777.e22. doi: 10.1016/j.cell.2025.03.008.
Bhargab Kalita 1,  Gerard Martinez-Cebrian 2,  Justina McEvoy 3,  Melody Allensworth 3,  Michelle Knight 4,  Alessandro Magli 5,  Rita C R Perlingeiro 6,  Michael A Dyer 3,  Elizabeth Stewart 7,  Brian David Dynlacht 8
Affiliations

Affiliations

  • 1 Department of Pathology and Perlmutter Cancer Institute, New York University School of Medicine, New York, NY 10016, USA. Electronic address: bhargab.kalita@nyulangone.org.
  • 2 Department of Pathology and Perlmutter Cancer Institute, New York University School of Medicine, New York, NY 10016, USA; Josep Carreras Leukaemia Research Institute, 08916 Badalona, Spain.
  • 3 Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 323, Memphis, TN 38105, USA.
  • 4 Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 323, Memphis, TN 38105, USA; Department of Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 5 Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA; Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA; Genomic Medicine Unit, Sanofi, 225nd Avenue, Waltham, MA 02451, USA.
  • 6 Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA.
  • 7 Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 323, Memphis, TN 38105, USA; Department of Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: elizabeth.stewart@stjude.org.
  • 8 Department of Pathology and Perlmutter Cancer Institute, New York University School of Medicine, New York, NY 10016, USA. Electronic address: brian.dynlacht@nyulangone.org.
PMID: 40185100 DOI: 10.1016/j.cell.2025.03.008
Abstract

Alveolar rhabdomyosarcoma (ARMS) patients harboring paired-box fusion proteins (PAX3/7-FOXO1) exhibit a greater incidence of tumor relapse, metastasis, and poor survival outcome, thereby underscoring the urgent need to develop effective therapies to treat this subtype of childhood Cancer. To uncover mechanisms that contribute to tumor initiation, we develop a muscle progenitor model and use epigenomic approaches to unravel genome rewiring events mediated by PAX3/7 fusion proteins. Among the key targets of PAX3/7 fusion proteins, we identify a cohort of oncogenes, Fibroblast Growth Factor (FGF) receptors, tRNA-modifying Enzymes, and genes essential for Mitochondrial Metabolism and protein translation, which we successfully targeted in preclinical trials. We identify leucine usage as a key factor driving the growth of aggressive PAX-fusion tumors, as limiting its bioavailability impaired Oxidative Phosphorylation and Mitochondrial Metabolism, delaying tumor progression and improving survival in vivo. Our data provide a compelling list of actionable targets and suggest promising new strategies to treat this tumor.

Keywords

3D/2D-adapted PDX models; Leucine; MYCN; TRMT5; alveolar rhabdomyosarcoma; mitochondrial metabolism; myogenic progenitors; roblitinib; tRNA modifications; tigecycline.

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