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

Cell. 2024 Apr 16:S0092-8674(24)00320-9. doi: 10.1016/j.cell.2024.03.029. Online ahead of print.

Authors

Alissa C Greenwald¹, Noam Galili Darnell¹, Rouven Hoefflin², Dor Simkin¹, Christopher W Mount³, L Nicolas Gonzalez Castro⁴, Yotam Harnik¹, Sydney Dumont³, Dana Hirsch⁵, Masashi Nomura³, Tom Talpir⁶, Merav Kedmi⁷, Inna Goliand⁷, Gioele Medici⁸, Julie Laffy¹, Baoguo Li⁹, Vamsi Mangena³, Hadas Keren-Shaul⁷, Michael Weller⁸, Yoseph Addadi⁷, Marian C Neidert¹⁰, Mario L Suvà¹¹, Itay Tirosh¹²

Affiliations

¹ Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
² Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel; Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
³ Department of Pathology, Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department of Pathology, Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
⁵ Immunohistochemistry Unit, Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel.
⁶ Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.
⁷ Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel.
⁸ Clinical Neuroscience Center, Department of Neurosurgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
⁹ Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel.
¹⁰ Clinical Neuroscience Center, Department of Neurosurgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Department of Neurosurgery, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
¹¹ Department of Pathology, Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: suva.mario@mgh.harvard.edu.
¹² Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. Electronic address: itay.tirosh@weizmann.ac.il.

PMID: 38653236
DOI: 10.1016/j.cell.2024.03.029

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.

Keywords: glioblastoma; glioma; hypoxia; intratumor heterogeneity; spatial proteomics; spatial transcriptomics.