Integrative spatial analysis reveals a multi-layered organization of glioblastoma

Alissa C. Greenwald; Noam Galili Darnell; Rouven Hoefflin; Dor Simkin; Christopher W. Mount; L. Nicolas Gonzalez Castro; Yotam Harnik; Sydney Dumont; Dana Hirsch; Masashi Nomura; Tom Talpir; Merav Kedmi; Inna Goliand; Gioele Medici; Julie Laffy; Baoguo Li; Vamsi Mangena; Hadas Keren-Shaul; Michael Weller; Yoseph Addadi; Marian C. Neidert; Mario L. Suvà; Itay Tirosh

doi:10.1016/j.cell.2024.03.029

Integrative spatial analysis reveals a multi-layered organization of glioblastoma

Alissa C. Greenwald
, Noam Galili Darnell
, Rouven Hoefflin
, Dor Simkin
, Christopher W. Mount
, L. Nicolas Gonzalez Castro
, Yotam Harnik
, Sydney Dumont
, Dana Hirsch
, Masashi Nomura
, Tom Talpir
, Merav Kedmi
, Inna Goliand
, Gioele Medici
, Julie Laffy
, Baoguo Li
, Vamsi Mangena
, Hadas Keren-Shaul
, Michael Weller
, Yoseph Addadi

Marian C. Neidert, Mario L. Suvà^*, Itay Tirosh^*

^*Corresponding author for this work

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

140 Citations (Scopus)

452 Downloads (Pure)

Abstract

Glioma contains malignant cells in diverse states. Here, we combine spatial transcriptomics, spatial proteomics, and computational approaches to define glioma cellular states and uncover their organization. We find three prominent modes of organization. First, gliomas are composed of small local environments, each typically enriched with one major cellular state. Second, specific pairs of states preferentially reside in proximity across multiple scales. This pairing of states is consistent across tumors. Third, these pairwise interactions collectively define a global architecture composed of five layers. Hypoxia appears to drive the layers, as it is associated with a long-range organization that includes all cancer cell states. Accordingly, tumor regions distant from any hypoxic/necrotic foci and tumors that lack hypoxia such as low-grade IDH-mutant glioma are less organized. In summary, we provide a conceptual framework for the organization of cellular states in glioma, highlighting hypoxia as a long-range tissue organizer.

Original language	English
Pages (from-to)	2485-2501.e26
Number of pages	44
Journal	Cell
Volume	187
Issue number	10
Early online date	22 Apr 2024
DOIs	https://doi.org/10.1016/j.cell.2024.03.029
Publication status	Published - 9 May 2024

Funding

This work was supported by the European Research Council Consolidator Grant 101044318 (to I.T.) and a Broad Institute-Israel Science Foundation Collaborative Project Award (to I.T. and M.L.S.). I.T. is the incumbent of the Dr. Celia Zwillenberg-Fridman and Dr. Lutz Zwillenberg Career Development Chair and is supported by the Zuckerman STEM Leadership Program, the Mexican Friends New Generation, the Benoziyo Endowment Fund, and the Israel Cancer Research Fund. The study was also supported by N.I.H. R37CA245523 and R01CA258763 (both to M.L.S.). R.H. is funded by the Walter Benjamin Programme from the German Research Foundation. N.G.D. is supported by the Israeli Council for Higher Education (CHE) via the Weizmann Data Science Research Center and by a research grant from the Estate of Tully and Michele Plesser. V.M. is supported by a NIH T32 Cancer Neuroscience Training Grant (T32CA272386). The images in this paper were acquired at the Advanced Optical Imaging Unit, de Picciotto-Lesser Cell Observatory Unit at the Moross Integrated Cancer Center Life Science Core Facilities, Weizmann Institute of Science. The authors would like to thank Dr. Ofra Golani for helpful discussions regarding image analysis and cell segmentation and Rony Chanoch-Myers and Rotem Tal for helpful feedback on the manuscript. The authors would like to thank Abcam for the generous donation of carrier-free antibodies for CODEX experiments. Publisher Copyright: © 2024 Elsevier Inc.

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.cell.2024.03.029Licence: CC BY

it_Cell_IntegrativeSpatialAnalysis_PV_2024Final published version, 19.7 MBLicence: CC BY

https://www.biorxiv.org/content/10.1101/2023.07.06.547924v1Licence: CC BY-NC-ND

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Greenwald, A. C., Darnell, N. G., Hoefflin, R., Simkin, D., Mount, C. W., Gonzalez Castro, L. N., Harnik, Y., Dumont, S., Hirsch, D., Nomura, M., Talpir, T., Kedmi, M., Goliand, I., Medici, G., Laffy, J., Li, B., Mangena, V., Keren-Shaul, H., Weller, M., ... Tirosh, I. (2024). Integrative spatial analysis reveals a multi-layered organization of glioblastoma. Cell, 187(10), 2485-2501.e26. https://doi.org/10.1016/j.cell.2024.03.029

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title = "Integrative spatial analysis reveals a multi-layered organization of glioblastoma",

abstract = "Glioma contains malignant cells in diverse states. Here, we combine spatial transcriptomics, spatial proteomics, and computational approaches to define glioma cellular states and uncover their organization. We find three prominent modes of organization. First, gliomas are composed of small local environments, each typically enriched with one major cellular state. Second, specific pairs of states preferentially reside in proximity across multiple scales. This pairing of states is consistent across tumors. Third, these pairwise interactions collectively define a global architecture composed of five layers. Hypoxia appears to drive the layers, as it is associated with a long-range organization that includes all cancer cell states. Accordingly, tumor regions distant from any hypoxic/necrotic foci and tumors that lack hypoxia such as low-grade IDH-mutant glioma are less organized. In summary, we provide a conceptual framework for the organization of cellular states in glioma, highlighting hypoxia as a long-range tissue organizer.",

author = "Greenwald, \{Alissa C.\} and Darnell, \{Noam Galili\} and Rouven Hoefflin and Dor Simkin and Mount, \{Christopher W.\} and \{Gonzalez Castro\}, \{L. Nicolas\} and Yotam Harnik and Sydney Dumont and Dana Hirsch and Masashi Nomura and Tom Talpir and Merav Kedmi and Inna Goliand and Gioele Medici and Julie Laffy and Baoguo Li and Vamsi Mangena and Hadas Keren-Shaul and Michael Weller and Yoseph Addadi and Neidert, \{Marian C.\} and Suv{\`a}, \{Mario L.\} and Itay Tirosh",

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month = may,

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Greenwald, AC, Darnell, NG , Hoefflin, R , Simkin, D, Mount, CW, Gonzalez Castro, LN, Harnik, Y, Dumont, S, Hirsch, D, Nomura, M, Talpir, T, Kedmi, M, Goliand, I, Medici, G, Laffy, J, Li, B, Mangena, V, Keren-Shaul, H, Weller, M, Addadi, Y, Neidert, MC, Suvà, ML & Tirosh, I 2024, 'Integrative spatial analysis reveals a multi-layered organization of glioblastoma', Cell, vol. 187, no. 10, pp. 2485-2501.e26. https://doi.org/10.1016/j.cell.2024.03.029

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AU - Greenwald, Alissa C.

AU - Darnell, Noam Galili

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AU - Simkin, Dor

AU - Mount, Christopher W.

AU - Gonzalez Castro, L. Nicolas

AU - Harnik, Yotam

AU - Dumont, Sydney

AU - Hirsch, Dana

AU - Nomura, Masashi

AU - Talpir, Tom

AU - Kedmi, Merav

AU - Goliand, Inna

AU - Medici, Gioele

AU - Laffy, Julie

AU - Li, Baoguo

AU - Mangena, Vamsi

AU - Keren-Shaul, Hadas

AU - Weller, Michael

AU - Addadi, Yoseph

AU - Neidert, Marian C.

AU - Suvà, Mario L.

AU - Tirosh, Itay

PY - 2024/5/9

Y1 - 2024/5/9

N2 - Glioma contains malignant cells in diverse states. Here, we combine spatial transcriptomics, spatial proteomics, and computational approaches to define glioma cellular states and uncover their organization. We find three prominent modes of organization. First, gliomas are composed of small local environments, each typically enriched with one major cellular state. Second, specific pairs of states preferentially reside in proximity across multiple scales. This pairing of states is consistent across tumors. Third, these pairwise interactions collectively define a global architecture composed of five layers. Hypoxia appears to drive the layers, as it is associated with a long-range organization that includes all cancer cell states. Accordingly, tumor regions distant from any hypoxic/necrotic foci and tumors that lack hypoxia such as low-grade IDH-mutant glioma are less organized. In summary, we provide a conceptual framework for the organization of cellular states in glioma, highlighting hypoxia as a long-range tissue organizer.

AB - Glioma contains malignant cells in diverse states. Here, we combine spatial transcriptomics, spatial proteomics, and computational approaches to define glioma cellular states and uncover their organization. We find three prominent modes of organization. First, gliomas are composed of small local environments, each typically enriched with one major cellular state. Second, specific pairs of states preferentially reside in proximity across multiple scales. This pairing of states is consistent across tumors. Third, these pairwise interactions collectively define a global architecture composed of five layers. Hypoxia appears to drive the layers, as it is associated with a long-range organization that includes all cancer cell states. Accordingly, tumor regions distant from any hypoxic/necrotic foci and tumors that lack hypoxia such as low-grade IDH-mutant glioma are less organized. In summary, we provide a conceptual framework for the organization of cellular states in glioma, highlighting hypoxia as a long-range tissue organizer.

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SP - 2485-2501.e26

JO - Cell

JF - Cell

IS - 10

ER -

Integrative spatial analysis reveals a multi-layered organization of glioblastoma

Abstract

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