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홍준희Jun-Hee Hong

국립암센터

Cancer Cell, January 11, 2024 | https://doi.org/10.1016/j.ccell.2023.12.015 Integrated proteogenomic characterization of glioblastoma evolution

Kyung-Hee Kim,^1,2,23 Simona Migliozzi,^3,23 Harim Koo,^1,4,5,23 Jun-Hee Hong,^1,23 Seung Min Park,¹ Sooheon Kim,¹ Hyung Joon Kwon,¹Seokjun Ha,¹ Luciano Garofano,³ Young Taek Oh,³ Fulvio D’Angelo,³ Chan Il Kim,¹ Seongsoo Kim,¹ Ji Yoon Lee,^4,5 Jiwon Kim,^4,5 Jisoo Hong,^4,5 Eun-Hae Jang,⁶ Bertrand Mathon,⁷ Anna-Luisa Di Stefano,^8,9,10,11 Franck Bielle,^8,9,10 Alice Laurenge,^8,9,10 Alexey I. Nesvizhskii,¹² Eun-Mi Hur,^6,13 Jinlong Yin,^1,14 Bingyang Shi,¹⁴ Youngwook Kim,¹ Kyung-Sub Moon,¹⁵Jeong Taik Kwon,¹⁶ Shin Heon Lee,¹⁶Seung Hoon Lee,¹⁷ Ho Shin Gwak,¹ Anna Lasorella,^3,18 Heon Yoo,¹ Marc Sanson,^8,9,10,* Jason K. Sa,^4,5,* Chul-Kee Park,^19,* Do-Hyun Nam,^20,* Antonio Iavarone,^3,21,*and Jong Bae Park ^1,22,24,*

¹Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Korea

²Proteomics Core Facility, Research Core Center, Research Institute, National Cancer Center, Goyang, Korea

³Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA

⁴Department of Biomedical Informatics, Korea University College of Medicine, Seoul, Korea

⁵Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Korea

⁶Laboratory of Neuroscience, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, Korea

⁷Service de Neurochirurgie, AP-HP, Hoˆ pitaux Universitaires La Pitie´ Salpeˆtrie`re - Charles Foix, Paris, France

⁸Institut de Neurologie, AP-HP, Hoˆ pitaux Universitaires La Pitie´ Salpeˆtrie`re - Charles Foix, Paris, France

⁹Sorbonne Universite´ , Inserm, CNRS, UMR S 1127, Paris Brain Institute (ICM), Equipe labellise´ e LNCC, Paris, France

¹⁰Onconeurotek, AP-HP, Hoˆ pital Pitie´-Salpeˆtrie`re, F-75013 Paris, France

¹¹Department of Neurology, Foch Hospital, Suresnes, France

¹²Department of Pathology, University of Michigan, Ann Arbor, MI, USA

¹³BK21 Four Future Veterinary Medicine Leading Education & Research Center, College of Veterinary Medicine, Seoul National University, Seoul, Korea

¹⁴Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, China

¹⁵Department of Neurosurgery, Chonnam National University Hwasun Hospital and Medical School, Hwasun, Korea

¹⁶Department of Neurosurgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Korea

¹⁷Department of Neurosurgery, Eulji University School of Medicine, Daejeon, Korea

¹⁸Department of Biochemistry, University of Miami Miller School of Medicine, Miami, FL, USA

¹⁹Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Korea

²⁰Department of Neurosurgery and Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

²¹Department of Neurological Surgery and Department of Biochemistry, University of Miami Miller School of Medicine, Miami, FL, USA

²²Department of Clinical Research, Research Institute and Hospital, National Cancer Center, Goyang, Korea

²³These authors contributed equally

²⁴Lead contact

^*Corresponding authors: correspondence to Marc Sanson, Jason K. Sa, Chul-Kee Park, Do-Hyun Nam, Antonio Iavarone or Jong Bae Park

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.

논문정보

형식Research article
게재일2024년 01월 (BRIC 등록일 2024-01-12)
연구진국내(교신)+국외 연구진
분야 생명과학 > 세포생물학

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