2. Academic Validation
  3. Integrated proteogenomic characterization of glioblastoma evolution

Integrated proteogenomic characterization of glioblastoma evolution

  • Cancer Cell. 2024 Jan 1:S1535-6108(23)00443-9. doi: 10.1016/j.ccell.2023.12.015.
Kyung-Hee Kim 1,  Simona Migliozzi 2,  Harim Koo 3,  Jun-Hee Hong 4,  Seung Min Park 4,  Sooheon Kim 4,  Hyung Joon Kwon 4,  Seokjun Ha 4,  Luciano Garofano 2,  Young Taek Oh 2,  Fulvio D'Angelo 2,  Chan Il Kim 4,  Seongsoo Kim 4,  Ji Yoon Lee 5,  Jiwon Kim 5,  Jisoo Hong 5,  Eun-Hae Jang 6,  Bertrand Mathon 7,  Anna-Luisa Di Stefano 8,  Franck Bielle 9,  Alice Laurenge 9,  Alexey I Nesvizhskii 10,  Eun-Mi Hur 11,  Jinlong Yin 12,  Bingyang Shi 13,  Youngwook Kim 4,  Kyung-Sub Moon 14,  Jeong Taik Kwon 15,  Shin Heon Lee 15,  Seung Hoon Lee 16,  Ho Shin Gwak 4,  Anna Lasorella 17,  Heon Yoo 4,  Marc Sanson 18,  Jason K Sa 19,  Chul-Kee Park 20,  Do-Hyun Nam 21,  Antonio Iavarone 22,  Jong Bae Park 23
Affiliations

Affiliations

  • 1 Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea; Proteomics Core Facility, Research Core Center, Research Institute, National Cancer Center, Goyang, Korea.
  • 2 Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 3 Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea; Department of Biomedical Informatics, Korea University College of Medicine, Seoul, Korea; Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Korea.
  • 4 Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea.
  • 5 Department of Biomedical Informatics, Korea University College of Medicine, Seoul, Korea; Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Korea.
  • 6 Laboratory of Neuroscience, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, Korea.
  • 7 Service de Neurochirurgie, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Paris, France.
  • 8 Institut de Neurologie, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Paris, France; Sorbonne Université, Inserm, CNRS, UMR S 1127, Paris Brain Institute (ICM), Equipe labellisée LNCC, Paris, France; Onconeurotek, AP-HP, Hôpital Pitié-Salpêtrière, F-75013 Paris, France; Department of Neurology, Foch Hospital, Suresnes, France.
  • 9 Institut de Neurologie, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Paris, France; Sorbonne Université, Inserm, CNRS, UMR S 1127, Paris Brain Institute (ICM), Equipe labellisée LNCC, Paris, France; Onconeurotek, AP-HP, Hôpital Pitié-Salpêtrière, F-75013 Paris, France.
  • 10 Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • 11 Laboratory of Neuroscience, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, Korea; BK21 Four Future Veterinary Medicine Leading Education & Research Center, College of Veterinary Medicine, Seoul National University, Seoul, Korea.
  • 12 Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea; Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, China.
  • 13 Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, China.
  • 14 Department of Neurosurgery, Chonnam National University Hwasun Hospital and Medical School, Hwasun, Korea.
  • 15 Department of Neurosurgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea.
  • 16 Department of Neurosurgery, Eulji University School of Medicine, Daejeon, Korea.
  • 17 Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Biochemistry, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 18 Institut de Neurologie, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Paris, France; Sorbonne Université, Inserm, CNRS, UMR S 1127, Paris Brain Institute (ICM), Equipe labellisée LNCC, Paris, France; Onconeurotek, AP-HP, Hôpital Pitié-Salpêtrière, F-75013 Paris, France. Electronic address: [email protected].
  • 19 Department of Biomedical Informatics, Korea University College of Medicine, Seoul, Korea; Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Korea. Electronic address: [email protected].
  • 20 Deparment of Neurosurgery, Seoul National University College of Medicine, Seoul, Korea. Electronic address: [email protected].
  • 21 Department of Neurosurgery and Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Electronic address: [email protected].
  • 22 Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Neurological Surgery and Department of Biochemistry, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address: [email protected].
  • 23 Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea; Department of Clinical Research, Research Institute and Hospital, National Cancer Center, Goyang, Korea. Electronic address: [email protected].
PMID: 38215747 DOI: 10.1016/j.ccell.2023.12.015
Abstract

The evolutionary trajectory of glioblastoma (GBM) is a multifaceted biological process that extends beyond genetic alterations alone. Here, we perform an integrative proteogenomic analysis of 123 longitudinal glioblastoma pairs and identify a highly proliferative cellular state at diagnosis and replacement by activation of neuronal transition and synaptogenic pathways in recurrent tumors. Proteomic and phosphoproteomic analyses reveal that the molecular transition to neuronal state at recurrence is marked by post-translational activation of the wingless-related integration site (Wnt)/ planar cell polarity (PCP) signaling pathway and BRaf protein kinase. Consistently, multi-omic analysis of patient-derived xenograft (PDX) models mirror similar patterns of evolutionary trajectory. Inhibition of B-raf proto-oncogene (BRaf) kinase impairs both neuronal transition and migration capability of recurrent tumor cells, phenotypic hallmarks of post-therapy progression. Combinatorial treatment of temozolomide (TMZ) with BRaf Inhibitor, vemurafenib, significantly extends the survival of PDX models. This study provides comprehensive insights into the biological mechanisms of glioblastoma evolution and treatment resistance, highlighting promising therapeutic strategies for clinical intervention.

Keywords

BRAF; longitudinal glioblastoma; neuronal; proteogenomics; recurrence; synapse.

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