1. Integrated proteogenomic characterization of glioblastoma evolution.
- Author
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Kim KH, Migliozzi S, Koo H, Hong JH, Park SM, Kim S, Kwon HJ, Ha S, Garofano L, Oh YT, D'Angelo F, Kim CI, Kim S, Lee JY, Kim J, Hong J, Jang EH, Mathon B, Di Stefano AL, Bielle F, Laurenge A, Nesvizhskii AI, Hur EM, Yin J, Shi B, Kim Y, Moon KS, Kwon JT, Lee SH, Lee SH, Gwak HS, Lasorella A, Yoo H, Sanson M, Sa JK, Park CK, Nam DH, Iavarone A, and Park JB
- Subjects
- Animals, Humans, Proto-Oncogene Proteins B-raf, Proteomics, Cell Line, Tumor, Neoplasm Recurrence, Local, Disease Models, Animal, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Glioblastoma genetics, Proteogenomics, Brain Neoplasms genetics
- 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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2024
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