Integrated proteogenomic characterization of glioblastoma evolution

Kyung Hee Kim; Simona Migliozzi; Harim Koo; Jun Hee Hong; Seung Min Park; Sooheon Kim; Hyung Joon Kwon; Seokjun Ha; Luciano Garofano; Young Taek Oh; Fulvio D'Angelo; Chan Il Kim; Seongsoo Kim; Ji Yoon Lee; Jiwon Kim; Jisoo Hong; Eun Hae Jang; Bertrand Mathon; Anna Luisa Di Stefano; Franck Bielle; Alice Laurenge; Alexey I. Nesvizhskii; Eun-Mi Hur; Jinlong Yin; Bingyang Shi; Youngwook Kim; Kyung Sub Moon; Jeong Taik Kwon; Shin Heon Lee; Seung Hoon Lee; Ho Shin Gwak; Anna Lasorella; Heon Yoo; Marc Sanson; Jason K. Sa; Chul-Kee Park; Do-Hyun Nam; Antonio Iavarone; Jong Bae Park

doi:10.1016/j.ccell.2023.12.015

Integrated proteogenomic characterization of glioblastoma evolution

Kyung Hee Kim, Simona Migliozzi, Harim Koo, Jun Hee Hong, Seung Min Park, Sooheon Kim, Hyung Joon Kwon, Seokjun Ha, Luciano Garofano, Young Taek Oh, Fulvio D'Angelo, Chan Il Kim, Seongsoo Kim, Ji Yoon Lee, Jiwon Kim, Jisoo Hong, Eun Hae Jang, Bertrand Mathon, Anna Luisa Di Stefano, Franck BielleAlice Laurenge, Alexey I. Nesvizhskii, Eun-Mi Hur, Jinlong Yin, Bingyang Shi, Youngwook Kim, Kyung Sub Moon, Jeong Taik Kwon, Shin Heon Lee, Seung Hoon Lee, Ho Shin Gwak, Anna Lasorella, Heon Yoo, Marc Sanson^*, Jason K. Sa^*, Chul-Kee Park^*, Do-Hyun Nam^*, Antonio Iavarone^*, Jong Bae Park^*

^*Corresponding author for this work

Macquarie Medical School

Research output: Contribution to journal › Article › peer-review

34 Citations (Scopus)

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.

Original language	English
Pages (from-to)	358-377.e8
Number of pages	29
Journal	Cancer Cell
Volume	42
Issue number	3
DOIs	https://doi.org/10.1016/j.ccell.2023.12.015
Publication status	Published - 11 Mar 2024

Keywords

BRAF
longitudinal glioblastoma
neuronal
proteogenomics
recurrence
synapse

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10.1016/j.ccell.2023.12.015

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Kim, K. H., Migliozzi, S., Koo, H., Hong, J. H., Park, S. M., Kim, S., Kwon, H. J., Ha, S., Garofano, L., Oh, Y. T., D'Angelo, F., Kim, C. I., Kim, S., Lee, J. Y., Kim, J., Hong, J., Jang, E. H., Mathon, B., Di Stefano, A. L., ... Park, J. B. (2024). Integrated proteogenomic characterization of glioblastoma evolution. Cancer Cell, 42(3), 358-377.e8. https://doi.org/10.1016/j.ccell.2023.12.015

@article{d2c80b8d68cb44ea8bd86727f219d8ef,

title = "Integrated proteogenomic characterization of glioblastoma evolution",

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",

author = "Kim, {Kyung Hee} and Simona Migliozzi and Harim Koo and Hong, {Jun Hee} and Park, {Seung Min} and Sooheon Kim and Kwon, {Hyung Joon} and Seokjun Ha and Luciano Garofano and Oh, {Young Taek} and Fulvio D'Angelo and Kim, {Chan Il} and Seongsoo Kim and Lee, {Ji Yoon} and Jiwon Kim and Jisoo Hong and Jang, {Eun Hae} and Bertrand Mathon and {Di Stefano}, {Anna Luisa} and Franck Bielle and Alice Laurenge and Nesvizhskii, {Alexey I.} and Eun-Mi Hur and Jinlong Yin and Bingyang Shi and Youngwook Kim and Moon, {Kyung Sub} and Kwon, {Jeong Taik} and Lee, {Shin Heon} and Lee, {Seung Hoon} and Gwak, {Ho Shin} and Anna Lasorella and Heon Yoo and Marc Sanson and Sa, {Jason K.} and Chul-Kee Park and Do-Hyun Nam and Antonio Iavarone and Park, {Jong Bae}",

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month = mar,

day = "11",

doi = "10.1016/j.ccell.2023.12.015",

language = "English",

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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, E-M, 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, C-K, Nam, D-H, Iavarone, A & Park, JB 2024, 'Integrated proteogenomic characterization of glioblastoma evolution', Cancer Cell, vol. 42, no. 3, pp. 358-377.e8. https://doi.org/10.1016/j.ccell.2023.12.015

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T1 - Integrated proteogenomic characterization of glioblastoma evolution

AU - Kim, Kyung Hee

AU - Migliozzi, Simona

AU - Koo, Harim

AU - Hong, Jun Hee

AU - Park, Seung Min

AU - Kim, Sooheon

AU - Kwon, Hyung Joon

AU - Ha, Seokjun

AU - Garofano, Luciano

AU - Oh, Young Taek

AU - D'Angelo, Fulvio

AU - Kim, Chan Il

AU - Kim, Seongsoo

AU - Lee, Ji Yoon

AU - Kim, Jiwon

AU - Hong, Jisoo

AU - Jang, Eun Hae

AU - Mathon, Bertrand

AU - Di Stefano, Anna Luisa

AU - Bielle, Franck

AU - Laurenge, Alice

AU - Nesvizhskii, Alexey I.

AU - Hur, Eun-Mi

AU - Yin, Jinlong

AU - Shi, Bingyang

AU - Kim, Youngwook

AU - Moon, Kyung Sub

AU - Kwon, Jeong Taik

AU - Lee, Shin Heon

AU - Lee, Seung Hoon

AU - Gwak, Ho Shin

AU - Lasorella, Anna

AU - Yoo, Heon

AU - Sanson, Marc

AU - Sa, Jason K.

AU - Park, Chul-Kee

AU - Nam, Do-Hyun

AU - Iavarone, Antonio

AU - Park, Jong Bae

PY - 2024/3/11

Y1 - 2024/3/11

N2 - 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.

AB - 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.

KW - BRAF

KW - longitudinal glioblastoma

KW - neuronal

KW - proteogenomics

KW - recurrence

KW - synapse

UR - http://www.scopus.com/inward/record.url?scp=85186192891&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2023.12.015

DO - 10.1016/j.ccell.2023.12.015

M3 - Article

C2 - 38215747

AN - SCOPUS:85186192891

SN - 1535-6108

VL - 42

SP - 358-377.e8

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -

Integrated proteogenomic characterization of glioblastoma evolution

Abstract

Keywords

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