2. Academic Validation
  3. Preclinical spheroid models identify BMX as a therapeutic target for metastatic MYCN nonamplified neuroblastoma

Preclinical spheroid models identify BMX as a therapeutic target for metastatic MYCN nonamplified neuroblastoma

  • JCI Insight. 2024 Jul 22;9(14):e169647. doi: 10.1172/jci.insight.169647.
Santhoshkumar Sundaramoorthy 1,  Daniele Filippo Colombo 2,  Rajendran Sanalkumar 1,  Liliane Broye 1,  Katia Balmas Bourloud 3,  Gaylor Boulay 4,  Luisa Cironi 1,  Ivan Stamenkovic 1,  Raffaele Renella 3,  Fabien Kuttler 5,  Gerardo Turcatti 5,  Miguel N Rivera 4,  Annick Mühlethaler-Mottet 3,  Anaïs Flore Bardet 6 7,  Nicolò Riggi 1
Affiliations

Affiliations

  • 1 Experimental Pathology Service, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
  • 2 Infectious Diseases Biomarkers, Janssen Research and Development, Beerse, Belgium.
  • 3 Department Woman-Mother-Child, Division of Pediatrics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
  • 4 Department of Pathology and Cancer Center, Massachusetts General Hospital and Harvard Medical School.
  • 5 Biomolecular Screening Facility, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
  • 6 Biotechnology and Cell Signaling (BSC), CNRS UMR7242, University of Strasbourg, Illkirch, France.
  • 7 Institute of Genetics and Molecular and Cellular Biology (IGBMC), CNRS UMR7104, University of Strasbourg, INSERM U1258, Illkirch, France.
PMID: 39133652 DOI: 10.1172/jci.insight.169647
Abstract

The development of targeted therapies offers new hope for patients affected by incurable Cancer. However, multiple challenges persist, notably in controlling tumor cell plasticity in patients with refractory and metastatic illness. Neuroblastoma (NB) is an aggressive pediatric malignancy originating from defective differentiation of neural crest-derived progenitors with oncogenic activity due to genetic and epigenetic alterations and remains a clinical challenge for high-risk patients. To identify critical genes driving NB aggressiveness, we performed combined chromatin and transcriptome analyses on matched patient-derived xenografts (PDXs), spheroids, and differentiated adherent cultures derived from metastatic MYCN nonamplified tumors. Bone marrow kinase on chromosome X (BMX) was identified among the most differentially regulated genes in PDXs and spheroids versus adherent models. BMX expression correlated with high tumor stage and poor patient survival and was crucial to the maintenance of the self-renewal and tumorigenic potential of NB spheroids. Moreover, BMX expression positively correlated with the mesenchymal NB cell phenotype, previously associated with increased chemoresistance. Finally, BMX inhibitors readily reversed this cellular state, increased the sensitivity of NB spheroids toward chemotherapy, and partially reduced tumor growth in a preclinical NB model. Altogether, our study identifies BMX as a promising innovative therapeutic target for patients with high-risk MYCN nonamplified NB.

Keywords

Cancer; Epigenetics; Oncogenes; Therapeutics.

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