한빛사논문
Simona Migliozzi1,2,17, Young Taek Oh1,2,17, Mohammad Hasanain1,2,17, Luciano Garofano1,2,17, Fulvio D’Angelo1,2, Ryan D. Najac1, Alberto Picca3,4, Franck Bielle4,5, Anna Luisa Di Stefano 4,6,7, Julie Lerond4, Jann N. Sarkaria 8, Michele Ceccarelli 9,10, Marc Sanson3,4,11, Anna Lasorella1,2,12,13,14,18 & Antonio Iavarone 1,2,12,15,16,18
1Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA.
2Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA.
3AP-HP, Hôpital de la Pitié-Salpêtrière, Service de Neurologie 2, Paris, France.
4Sorbonne Université, INSERM Unité 1127, CNRS UMR 7225, Paris Brain Institute, Equipe labellissée LNCC, Paris, France.
5Department of Neuropathology, Pitié-Salpêtrière–Charles Foix, AP-HP, Paris, France.
6Department of Neurology, Foch Hospital, Suresnes, Paris, France.
7Neurosurgery Unit, Spedali Riuniti, Livorno, Italy.
8Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.
9Department of Electrical Engineering and Information Technology (DIETI), University of Naples Federico II, Napoli, Italy.
10BIOGEM Institute of Molecular Biology and Genetics, Via Camporeale, Ariano Irpino, Italy.
11Onconeurotek Tumor Bank, Paris Brain Institute ICM, Paris, France.
12Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
13Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
14Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL, USA.
15Department of Neurology, Columbia University Medical Center, New York, NY, USA.
16Department of Neurological Surgery, University of Miami, Miller School of Medicine, Miami, FL, USA.
17These authors contributed equally: Simona Migliozzi, Young Taek Oh, Mohammad Hasanain, Luciano Garofano.
18These authors jointly supervised this work: Anna Lasorella, Antonio Iavarone.
Corresponding authors : Correspondence to Anna Lasorella or Antonio Iavarone.
Abstract
Despite producing a panoply of potential cancer-specific targets, the proteogenomic characterization of human tumors has yet to demonstrate value for precision cancer medicine. Integrative multi-omics using a machine-learning network identified master kinases responsible for effecting phenotypic hallmarks of functional glioblastoma subtypes. In subtype-matched patient-derived models, we validated PKCδ and DNA-PK as master kinases of glycolytic/plurimetabolic and proliferative/progenitor subtypes, respectively, and qualified the kinases as potent and actionable glioblastoma subtype-specific therapeutic targets. Glioblastoma subtypes were associated with clinical and radiomics features, orthogonally validated by proteomics, phospho-proteomics, metabolomics, lipidomics and acetylomics analyses, and recapitulated in pediatric glioma, breast and lung squamous cell carcinoma, including subtype specificity of PKCδ and DNA-PK activity. We developed a probabilistic classification tool that performs optimally with RNA from frozen and paraffin-embedded tissues, which can be used to evaluate the association of therapeutic response with glioblastoma subtypes and to inform patient selection in prospective clinical trials.
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