Deciphering spatial cellular heterogeneity in glioblastoma
Hematology, Oncology
Final Report Abstract
Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Intra-tumor heterogeneity (ITH) is a hallmark of GBM, influencing key biological properties such as progression, therapy resistance, and recurrence. GBM has been extensively characterized using single-cell RNA sequencing, identifying four recurrent cancer cell states present in all GBMs. This emphasizes the high degree of plasticity that is closely linked to the tumor microenvironment (TME). However, the spatial organization of these malignant cell states in conjunction with the nonmalignant cells of the TME remained unclear. My postdoctoral goal at Prof. Itay Tirosh's laboratory at the Weizmann Institute was to establish new spatial single-cell technologies and advanced computational methods to create a quantitative framework for deciphering the spatial architecture of GBM. I established two novel spatial single-cell technologies: i) spatial transcriptomics (10X Visium) and ii) spatial proteomics (Co-detection by Indexing, CODEX), characterizing 25 GBMs. I then developed new bioinformatic methods to define a spatial model of GBM. Our evaluation showed that specific tumor regions are either organized or disorganized, driven by hypoxia and necrosis, inducing GBM cells to arrange into five spatial layers. Regions far from hypoxia, however, are chaotic and lack substantial structure. Importantly, the organization induced by hypoxia extends beyond the classical histopathological features associated with hypoxia, thus invisible in routine H&E stains. In summary, this work provides a holistic model of the spatial architecture of GBM, highlighting the essential role of hypoxia in spatial organization. This adds a spatial dimension to our growing understanding of the glioma ecosystem and will aid in developing new therapies.
Publications
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Hallmarks of transcriptional intratumour heterogeneity across a thousand tumours. Nature, 618(7965), 598-606.
Gavish, Avishai; Tyler, Michael; Greenwald, Alissa C.; Hoefflin, Rouven; Simkin, Dor; Tschernichovsky, Roi; Galili, Darnell Noam; Somech, Einav; Barbolin, Chaya; Antman, Tomer; Kovarsky, Daniel; Barrett, Thomas; Gonzalez, Castro L. Nicolas; Halder, Debdatta; Chanoch-Myers, Rony; Laffy, Julie; Mints, Michael; Wider, Adi; Tal, Rotem ... & Tirosh, Itay
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Integrative spatial analysis reveals a multi-layered organization of glioblastoma. openRxiv.
Greenwald, Alissa C.; Darnell, Noam Galili; Hoefflin, Rouven; Simkin, Dor; Gonzalez-Castro, L. Nicolas; Mount, Christopher; Hirsch, Dana; Nomura, Masashi; Talpir, Tom; Kedmi, Merav; Goliand, Inna; Medici, Gioele; Li, Baoguo; Keren-Shaul, Hadas; Weller, Michael; Addadi, Yoseph; Neidert, Marian C.; Suvá, Mario L. & Tirosh, Itay
