Year: 2022
Type: conference-abstract
Abstract: Histone 3 lysine27-to-methionine mutant diffuse midline gliomas (H3-K27M DMGs) are among the most lethal brain tumors. Their putative cellular hierarchy has been shown to be driven by self-renewing stem-like cells arrested in an oligodendrocyte precursor-like (OPC-like) state, of which few cells are able to differentiate towards more mature astrocyte (AC)-like and oligodendrocyte (OC)-like cells. However, the spatial organization underlying this tumor cell architecture and its microenvironmental interactions in intact H3-K27M DMG tissues remain unknown. Here, we profiled the single cell transcriptomes of 45 patient H3-K27M DMGs and derived cell population-specific marker gene combinations to characterize the single cell spatial organization of 16 tumors using targeted in situ sequencing. We thereby resolved different malignant and non-malignant cell populations including cycling, OPC-like, AC-like, OC-like, mesenchymal tumor cells, and non-malignant oligodendrocytes, astrocytes, neurons, myeloid cells, T cells, and vascular cells directly in situ. Global neighborhood analyses indicate a higher tendency of cycling OPC-like cells, vascular cells, and neurons to localize within a more restricted homogeneous compartment, whereas AC-like cells, non-malignant astrocytes and myeloid cells tend to intermingle with different cell populations in a more diffuse manner. Among malignant cells, we observed cycling OPC-like and OC-like cells to co-localize within a niche-like structure that is surrounded by more differentiated AC-like cells. We further validated this stem-like niche at the protein level using multiplexed immunofluorescence via the CODEX system. Finally, we characterized relationships between malignant and non-malignant cells, consistently identifying preferred neighborhoods of mesenchymal tumor cells with vascular and myeloid cells. Together, this study resolves the spatial architecture of H3-K27M DMG malignant and non-malignant cells at single cell resolution and identifies a local niche of the oligodendroglial lineage containing the OPC-like cancer stem-like cells, thus providing novel insights into the cancer stem-like compartment in H3-K27M DMGs and suggesting potential avenues for its perturbation.
Source: Neuro-Oncology
Authors: Ilon Liu, Jiang Li, Erik Samuelsson, Sergio Marco Salas, Alexander Beck, Olivia Hack, Daeun Jeong, McKenzie Shaw, Bernhard Englinger, Jenna Labelle, Hafsa Mire, Sibylle Madlener, Lisa Mayr, Michael Quezada, Maria Trissal, Eshini Panditharatna, Kati Ernst, Taylor Gatesman, Matthew Halbert, Hana Palova, Petra Pokorna, Jaroslav Sterba, Ondrej Slaby, Rene Geyeregger, Aaron Diaz, Adam C Resnick, Mario Suva, David Jones, Sameer Agnihotri, Jessica Ostlin, Carl Koschmann, Christine Haberler, Thomas Czech, Irene Slavc, Jennifer Cotter, Keith Ligon, Sanda Alexandrescu, W K Alfred Yung, Isabel Arrillaga-Romany, Johannes Gojo, Michelle Monje, Mats Nilsson, Mariella Filbin
Institutions: Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Science for Life Laboratory, Ludwig-Maximilians-Universität München, Dana-Farber Cancer Institute, Medical University of Vienna, Stanford University, German Cancer Research Center, University of Pittsburgh, Masaryk University, Central European Institute of Technology, Central European Institute of Technology – Masaryk University, University of California, San Francisco, Children's Hospital of Philadelphia, MGH Institute of Health Professions, Stockholm University, University of Michigan, Michigan Medicine, Children's Hospital of Los Angeles, The University of Texas MD Anderson Cancer Center, Massachusetts General Hospital
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4309014875