Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective

Radhika Mathur; Qixuan Wang; Patrick G. Schupp; Ana Nikolic; Stephanie Hilz; Chibo Hong; Nadia R. Grishanina; Darwin Kwok; Nicholas O. Stevers; Qiushi Jin; Mark W. Youngblood; Lena Ann Stasiak; Ye Hou; Juan Wang; Takafumi N. Yamaguchi; Marisa Lafontaine; Anny Shai; Ivan V. Smirnov; David A. Solomon; Susan M. Chang; Shawn L. Hervey-Jumper; Mitchel S. Berger; Janine M. Lupo; Hideho Okada; Joanna J. Phillips; Paul C. Boutros; Marco Gallo; Michael C. Oldham; Feng Yue; Joseph F. Costello

doi:10.1016/j.cell.2023.12.013

Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective

Radhika Mathur, Qixuan Wang, Patrick G. Schupp, Ana Nikolic, Stephanie Hilz, Chibo Hong, Nadia R. Grishanina, Darwin Kwok, Nicholas O. Stevers, Qiushi Jin, Mark W. Youngblood, Lena Ann Stasiak, Ye Hou, Juan Wang, Takafumi N. Yamaguchi, Marisa Lafontaine, Anny Shai, Ivan V. Smirnov, David A. Solomon, Susan M. ChangShawn L. Hervey-Jumper, Mitchel S. Berger, Janine M. Lupo, Hideho Okada, Joanna J. Phillips, Paul C. Boutros, Marco Gallo, Michael C. Oldham, Feng Yue^*, Joseph F. Costello^*

^*Corresponding author for this work

Biochemistry and Molecular Genetics

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

33 Scopus citations

Abstract

Treatment failure for the lethal brain tumor glioblastoma (GBM) is attributed to intratumoral heterogeneity and tumor evolution. We utilized 3D neuronavigation during surgical resection to acquire samples representing the whole tumor mapped by 3D spatial coordinates. Integrative tissue and single-cell analysis revealed sources of genomic, epigenomic, and microenvironmental intratumoral heterogeneity and their spatial patterning. By distinguishing tumor-wide molecular features from those with regional specificity, we inferred GBM evolutionary trajectories from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions. Our work depicts GBM evolution and heterogeneity from a 3D whole-tumor perspective, highlights potential therapeutic targets that might circumvent heterogeneity-related failures, and establishes an interactive platform enabling 360° visualization and analysis of 3D spatial patterns for user-selected genes, programs, and other features across whole GBM tumors.

Original language	English (US)
Pages (from-to)	446-463.e16
Journal	Cell
Volume	187
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2023.12.013
State	Published - Jan 18 2024

Funding

We thank the patients and their families for consent to collect and use tumor samples. We thank the staff of the University of California, San Francisco’s Brain Tumor Center Tissue Bank for sample acquisition and histopathology services and the Center for Advanced Technology for sequencing services. This project was supported by a gift from the Hana Jabsheh Research Initiative and the Panattoni family . Additional support provided by the Brain Tumor Funders' Collaborative (J.F.C.), National Institutes of Health Grants F32 1F32CA239472-01 (R.M), T32 T32CA151022 (R.M., S.H.), R01 CA169316 (to J.F.C.), P01 CA118816-06 (to J.F.C., J.M.L, J.J.P.), R50 CA274229 (to C. H.), P50 CA097257 (to J.J.P., and J.F.C.), U01 CA229345 (to J.J.P.); and the Chan Zuckerberg (CZ) Biohub. F.Y. was supported by NIH grants R35GM124820 , 1R01HG009906 , and R01HG011207 .

Keywords

brain tumors
chromatin accessibility
chromatin interactions
epigenomics
genomics
glioblastoma
intratumoral heterogeneity
microenvironment
spatial analysis
tumor evolution

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Mathur, R., Wang, Q., Schupp, P. G., Nikolic, A., Hilz, S., Hong, C., Grishanina, N. R., Kwok, D., Stevers, N. O., Jin, Q., Youngblood, M. W., Stasiak, L. A., Hou, Y., Wang, J., Yamaguchi, T. N., Lafontaine, M., Shai, A., Smirnov, I. V., Solomon, D. A., ... Costello, J. F. (2024). Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective. Cell, 187(2), 446-463.e16. https://doi.org/10.1016/j.cell.2023.12.013

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title = "Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective",

abstract = "Treatment failure for the lethal brain tumor glioblastoma (GBM) is attributed to intratumoral heterogeneity and tumor evolution. We utilized 3D neuronavigation during surgical resection to acquire samples representing the whole tumor mapped by 3D spatial coordinates. Integrative tissue and single-cell analysis revealed sources of genomic, epigenomic, and microenvironmental intratumoral heterogeneity and their spatial patterning. By distinguishing tumor-wide molecular features from those with regional specificity, we inferred GBM evolutionary trajectories from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions. Our work depicts GBM evolution and heterogeneity from a 3D whole-tumor perspective, highlights potential therapeutic targets that might circumvent heterogeneity-related failures, and establishes an interactive platform enabling 360° visualization and analysis of 3D spatial patterns for user-selected genes, programs, and other features across whole GBM tumors.",

keywords = "brain tumors, chromatin accessibility, chromatin interactions, epigenomics, genomics, glioblastoma, intratumoral heterogeneity, microenvironment, spatial analysis, tumor evolution",

author = "Radhika Mathur and Qixuan Wang and Schupp, {Patrick G.} and Ana Nikolic and Stephanie Hilz and Chibo Hong and Grishanina, {Nadia R.} and Darwin Kwok and Stevers, {Nicholas O.} and Qiushi Jin and Youngblood, {Mark W.} and Stasiak, {Lena Ann} and Ye Hou and Juan Wang and Yamaguchi, {Takafumi N.} and Marisa Lafontaine and Anny Shai and Smirnov, {Ivan V.} and Solomon, {David A.} and Chang, {Susan M.} and Hervey-Jumper, {Shawn L.} and Berger, {Mitchel S.} and Lupo, {Janine M.} and Hideho Okada and Phillips, {Joanna J.} and Boutros, {Paul C.} and Marco Gallo and Oldham, {Michael C.} and Feng Yue and Costello, {Joseph F.}",

note = "Publisher Copyright: {\textcopyright} 2023",

year = "2024",

month = jan,

day = "18",

doi = "10.1016/j.cell.2023.12.013",

language = "English (US)",

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Mathur, R, Wang, Q, Schupp, PG, Nikolic, A, Hilz, S, Hong, C, Grishanina, NR, Kwok, D, Stevers, NO, Jin, Q, Youngblood, MW, Stasiak, LA, Hou, Y, Wang, J, Yamaguchi, TN, Lafontaine, M, Shai, A, Smirnov, IV, Solomon, DA, Chang, SM, Hervey-Jumper, SL, Berger, MS, Lupo, JM, Okada, H, Phillips, JJ, Boutros, PC, Gallo, M, Oldham, MC, Yue, F & Costello, JF 2024, 'Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective', Cell, vol. 187, no. 2, pp. 446-463.e16. https://doi.org/10.1016/j.cell.2023.12.013

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T1 - Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective

AU - Mathur, Radhika

AU - Wang, Qixuan

AU - Schupp, Patrick G.

AU - Nikolic, Ana

AU - Hilz, Stephanie

AU - Hong, Chibo

AU - Grishanina, Nadia R.

AU - Kwok, Darwin

AU - Stevers, Nicholas O.

AU - Jin, Qiushi

AU - Youngblood, Mark W.

AU - Stasiak, Lena Ann

AU - Hou, Ye

AU - Wang, Juan

AU - Yamaguchi, Takafumi N.

AU - Lafontaine, Marisa

AU - Shai, Anny

AU - Smirnov, Ivan V.

AU - Solomon, David A.

AU - Chang, Susan M.

AU - Hervey-Jumper, Shawn L.

AU - Berger, Mitchel S.

AU - Lupo, Janine M.

AU - Okada, Hideho

AU - Phillips, Joanna J.

AU - Boutros, Paul C.

AU - Gallo, Marco

AU - Oldham, Michael C.

AU - Yue, Feng

AU - Costello, Joseph F.

PY - 2024/1/18

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N2 - Treatment failure for the lethal brain tumor glioblastoma (GBM) is attributed to intratumoral heterogeneity and tumor evolution. We utilized 3D neuronavigation during surgical resection to acquire samples representing the whole tumor mapped by 3D spatial coordinates. Integrative tissue and single-cell analysis revealed sources of genomic, epigenomic, and microenvironmental intratumoral heterogeneity and their spatial patterning. By distinguishing tumor-wide molecular features from those with regional specificity, we inferred GBM evolutionary trajectories from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions. Our work depicts GBM evolution and heterogeneity from a 3D whole-tumor perspective, highlights potential therapeutic targets that might circumvent heterogeneity-related failures, and establishes an interactive platform enabling 360° visualization and analysis of 3D spatial patterns for user-selected genes, programs, and other features across whole GBM tumors.

AB - Treatment failure for the lethal brain tumor glioblastoma (GBM) is attributed to intratumoral heterogeneity and tumor evolution. We utilized 3D neuronavigation during surgical resection to acquire samples representing the whole tumor mapped by 3D spatial coordinates. Integrative tissue and single-cell analysis revealed sources of genomic, epigenomic, and microenvironmental intratumoral heterogeneity and their spatial patterning. By distinguishing tumor-wide molecular features from those with regional specificity, we inferred GBM evolutionary trajectories from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions. Our work depicts GBM evolution and heterogeneity from a 3D whole-tumor perspective, highlights potential therapeutic targets that might circumvent heterogeneity-related failures, and establishes an interactive platform enabling 360° visualization and analysis of 3D spatial patterns for user-selected genes, programs, and other features across whole GBM tumors.

KW - brain tumors

KW - chromatin accessibility

KW - chromatin interactions

KW - epigenomics

KW - genomics

KW - glioblastoma

KW - intratumoral heterogeneity

KW - microenvironment

KW - spatial analysis

KW - tumor evolution

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SN - 0092-8674

VL - 187

SP - 446-463.e16

JO - Cell

JF - Cell

IS - 2

ER -

Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective

Abstract

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