Multiomic integration reveals tumoral heterogeneity of lipid dependence within lethal group 3 medulloblastoma PMID: 41544627

ADC Targets in Oncology

2026-04-10

Multiomic integration reveals tumoral heterogeneity of lipid dependence within lethal group 3 medulloblastoma

Cancer Cell. 2026 Feb 9;44(2):383-404.e18. doi: 10.1016/j.ccell.2025.12.012.

Flavia Bernardi ¹ , Jacob Torrejon ¹ , Irene Basili ² , Randy Van Ommeren ³ , Véronique Marsaud ⁴ , Hua Yu ⁴ , Julie Talbot ¹ , Judith Souphron ¹ , Emilie Indersie ⁴ , Antoine Forget ⁴ , Benjamin Bonneau ⁵ , Alexane Massiot ¹ , Coralie Alcazar ⁶ , Laurine Figeac ¹ , Emma Bonerandi ¹ , Gabriele Cancila ⁴ , Olga Sirbu ⁷ , Navneesh Yadav ⁸ , Dinesh Mohanakrishnan ⁸ , Bérangère Lombard ⁹ , Damarys Loew ⁹ , Patrick Poullet ¹⁰ , Stephane Liva ¹⁰ , Marta Lovino ¹¹ , I-Hsuan Lin ¹² , Takuma Nakashima ¹³ , Tarek Gharsalli ¹⁴ , Paul Antoine Nicolas ¹⁰ , Naoji Yubuki ¹⁵ , Roberto A Ribas ¹⁶ , Benoit Colsch ¹⁷ , Emeline Chu-Van ¹⁷ , Florence Castelli ¹⁷ , Julio Lopes Sampaio ¹⁸ , Sophie Leboucher ¹⁹ , Charlene Lasgi ²⁰ , Laetitia Besse ¹⁵ , Marie-Noëlle Soler ¹⁵ , Valentina Lo Re ¹ , Nathalie Planque ²¹ , Namal Abeysundara ²² , Polina Balin ²³ , Hao Wang ²² , Haipeng Su ²³ , Xiaochong Wu ²³ , Florence M G Cavalli ¹⁰ , Olivier Saulnier ²⁴ , Elisa Ficarra ¹¹ , Lucia Di Marcotullio ²⁵ , Kohei Kumegawa ²⁶ , Reo Maruyama ²⁷ , Daisuke Kawauchi ²⁸ , Daniel Picard ²⁹ , Marc Remke ²⁹ , Laurent Riffaud ³⁰ , Chloé Puiseux ³¹ , Yassine Bouchoucha ³² , Sophie Huybrechts ³³ , Marie Simbozel ³⁴ , Franck Bourdeaut ³⁵ , Pascale Varlet ³⁶ , Stéphanie Puget ³⁷ , Thomas Blauwblomme ³⁷ , Mamy Andrianteranagna ¹⁰ , Julien Masliah Planchon ³⁸ , Aurelien Dugourd ³⁹ , Julio Saez-Rodriguez ⁴⁰ , Emmanuel Barillot ¹⁰ , Nicolas Servant ¹⁰ , Loredana Martignetti ¹⁰ , Jeremy Rich ⁴¹ , Marcel Kool ⁴² , Stefan M Pfister ⁴³ , Sameer Agnihotri ⁴⁴ , Hiromichi Suzuki ¹³ , Marjorie Fanjul ⁴⁵ , Won-Jing Wang ¹² , Jin-Wu Tsai ⁴⁶ , Ramon C Sun ¹⁶ , Kévin Beccaria ³⁷ , Christelle Dufour ⁴⁷ , Jean-Emmanuel Sarry ⁴⁸ , Kulandaimanuvel Antony Michealraj ⁴⁹ , Michael D Taylor ⁵⁰ , Olivier Ayrault ⁵¹

Affiliations

1. Institut Curie, PSL Research University, INSERM U1330/CNRS EMR 8001, Children's Oncology Research Unit (CONCERT), Equipe Labellisée LIGUE 2024, Paris, France; Université Paris-Saclay, INSERM U1330/CNRS EMR 8001, Children's Oncology Research Unit (CONCERT), Equipe Labellisée LIGUE 2024, Orsay, France.
2. Institut Curie, PSL Research University, INSERM U1330/CNRS EMR 8001, Children's Oncology Research Unit (CONCERT), Equipe Labellisée LIGUE 2024, Paris, France; Université Paris-Saclay, INSERM U1330/CNRS EMR 8001, Children's Oncology Research Unit (CONCERT), Equipe Labellisée LIGUE 2024, Orsay, France; Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome La Sapienza, 00161, Rome, Italy.
3. Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
4. Institut Curie, PSL Research University, Orsay, France; CNRS UMR 3347, INSERM U1021, Université Paris-Saclay, Orsay, France.
5. Université Paris-Saclay, INSERM U1330/CNRS EMR 8001, Children's Oncology Research Unit (CONCERT), Equipe Labellisée LIGUE 2024, Orsay, France.
6. Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm, CNRS, Equipe Labellisée LIGUE 2023, Toulouse, France; Labex TOuCAN, Toulouse, France.
7. Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
8. Department of Neurological surgery, University of Pittsburgh School of Medicine, and Cancer biology Program, UPMC Hillman Cancer center, Pittsburgh, PA, USA.
9. Institut Curie, PSL Research University, Centre de Recherche, Laboratoire de Spectrométrie de Masse Protéomique, 26 rue d'Ulm, 75248 Paris, France.
10. Institut Curie, INSERM U1331, MINES ParisTech, PSL Research University, Paris, France.
11. Dipartimento di Ingegneria Enzo Ferrari, University of Modena and Reggio Emilia, Modena, Italy.
12. Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan.
13. Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan.
14. Inovarion, Paris, France.
15. Institut Curie, PSL University, CNRS UAR2016, INSERM US43, Université Paris-Saclay, Multimodal Imaging Center, 91400 Orsay, France.
16. Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, FL 32610, USA.
17. Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (MTS), MetaboHUB, Gif sur Yvette, France.
18. Institut Curie, CurieCoreTech Metabolomics and Lipidomics platform, Paris, France.
19. Institut Curie, Histology Facility, Orsay 91400, France.
20. Institut Curie, Cytometry Platform, Orsay 91400, France.
21. Institut Curie, PSL Research University, INSERM U1330/CNRS EMR 8001, Children's Oncology Research Unit (CONCERT), Equipe Labellisée LIGUE 2024, Paris, France; Université Paris-Saclay, INSERM U1330/CNRS EMR 8001, Children's Oncology Research Unit (CONCERT), Equipe Labellisée LIGUE 2024, Orsay, France; Université Paris Cité, France.
22. The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
23. Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, USA.
24. INSERM U1330, Genomics and Development of Childhood Cancers Lab, Institut Curie, PSL University, SIREDO Oncology Center, Paris, France.
25. Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome La Sapienza, 00161, Rome, Italy; Department of Molecular Medicine, University of Rome La Sapienza, 00161 Rome, Italy.
26. Cancer Cell Diversity Project, NEXT-Ganken Program, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
27. Project for Cancer Epigenomics, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
28. Department of Neuro-oncology, Institute of Brain Science, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan.
29. Department of Pediatric Oncology and Hematology, Saarland University Medical Center, Homburg, Germany.
30. Department of Pediatric Neurosurgery, Rennes University Hospital, Rennes, France.
31. Department of Pediatric Oncology, Rennes University Hospital, Rennes, France.
32. SIREDO: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, 75005 Paris, France.
33. Department of Pediatric Hemato-Oncology, National Center for Pediatrics, Centre Hospitalier du Luxembourg, Luxembourg City, Luxembourg.
34. Department of Child and Adolescents Oncology, Gustave Roussy, Université Paris-Saclay, 94805 Villejuif, France.
35. SIREDO: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie, 75005 Paris, France; Institut Curie, INSERM U1330, Children's Oncology Research Unit (CONCERT), Université Paris Cité, Paris, France.
36. Department of Neuropathology, GHU Paris-Psychiatrie et Neurosciences, Sainte-Anne Hospital, Paris, France; UMR 1266, IMA-Brain, Institut de Psychiatrie et Neurosciences de Paris, Inserm, Paris, France.
37. Department of Pediatric Neurosurgery, Necker Enfants Malades Hospital, APHP, Université Paris Cité, Paris, France.
38. Unit of Somatic Genetics, Institut Curie, Paris, France.
39. Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg, Germany.
40. Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Heidelberg, Germany; European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridgeshire, UK.
41. Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
42. Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany; Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany; University Medical Center Utrecht (UMCU), Utrecht, the Netherlands.
43. Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany; National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany; Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany.
44. University of Pittsburgh, Department of Neurological Surgery, Pittsburgh, PA, USA.
45. Université Toulouse, CNRS, Inserm, CRCT, Equipe labellisée Ligue Contre le Cancer, Toulouse, France.
46. Institute of Brain Science, Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan.
47. Department of Child and Adolescents Oncology, Gustave Roussy, Université Paris-Saclay, 94805 Villejuif, France; INSERM U981, Molecular Predictors and New Targets in Oncology, University Paris-Saclay, Villejuif, France.
48. Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm, CNRS, Equipe Labellisée LIGUE 2023, Toulouse, France; Labex TOuCAN, Toulouse, France. Electronic address: [email protected].
49. Department of Neurological surgery, University of Pittsburgh School of Medicine, and Cancer biology Program, UPMC Hillman Cancer center, Pittsburgh, PA, USA. Electronic address: [email protected].
50. Division of Neurosurgery, Department of Surgery, Texas Children's Hospital, Houston, TX, USA; Neuro-oncology Research Program, Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, USA. Electronic address: [email protected].
51. Institut Curie, PSL Research University, INSERM U1330/CNRS EMR 8001, Children's Oncology Research Unit (CONCERT), Equipe Labellisée LIGUE 2024, Paris, France; Université Paris-Saclay, INSERM U1330/CNRS EMR 8001, Children's Oncology Research Unit (CONCERT), Equipe Labellisée LIGUE 2024, Orsay, France. Electronic address: [email protected].

Abstract

Medulloblastoma, the most common malignant brain tumor of childhood, exhibits significant biological complexity that demands deeper exploration. Here, we present a large multiomics dataset integrating data from 384 primary medulloblastoma patient samples across five omic layers: CpG methylome, transcriptome, proteome, phosphoproteome, and metabolome, paired with associated clinical metadata. Data integration revealed intertumoral heterogeneity of lipid metabolism across proteomic subtypes. Notably, while the MYC-FASN-SCD axis drives lipid biosynthesis, pathway inhibition elicits a compensatory escape mechanism in vivo through exogenous fatty acid uptake. Unexpectedly, we demonstrated that MYC triggers lipid storage, creating a unique dependency on lipid droplet-mitochondria communications to sustain tumor maintenance in vivo. Together, this comprehensive analysis reveals a targetable vulnerability downstream of MYC that constitutes a promising therapeutic approach to treat currently untreatable medulloblastoma subtypes.

Keywords

lipid biosynthesis; lipid droplets; lipid oxidative stress; medulloblastoma; metabolomics; multiomics integration; pediatric cancer; phosphoproteomics; proteomics; transcriptomics.