EPEN-29. Spatial transcriptomic analysis of ependymoma implicates unresolved wound healing as a driver of tumor progression. (3rd June 2022)

• Record Type: Journal Article
• Authors: Donson, Andrew; Fu, Rui; Norris, gregory; Willard, Nicholas; Griesinger, Andrea; Riemondy, Kent; Amani, Vladimir; Grimaldo, Enrique; Harris, Faith; Hankinson, Todd; Mitra, Siddhartha; Ritzmann, timothy; Grundy, Richard; Foreman, Nicholas
• Is Part Of: Neuro-oncology. Volume 24(2022)Supplement 1
• Page Start: i45
• Page End: i45
• Publication Date: 2022-06-03
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noac079.165
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Ependymoma is a childhood brain tumor that remains incurable in approximately 50 percent of cases, most commonly in posterior fossa subgroup A (PFA). Uncovering how heterogeneous cell types within the tumor microenvironment (TME) interact is crucial to a complete understanding of PFA disease progression. The underlying cellular components of the PFA TME have been revealed by single-cell RNAseq (scRNAseq), identifying divergent epithelial differentiation and epithelial-mesenchymal transition (EMT) lineages. Here, we utilize spatial transcriptomics (Visium) of 14 PFA samples, integrated with scRNAseq, to chart neoplastic and immune cell architecture, with a higher resolution of cellular heterogeneity than scRNAseq alone. At a gross level, all PFA were primarily comprised of neoplastic epithelial and mesenchymal transcriptomic spatial zones, each containing a diversity of hierarchical cellular stages. In all samples we revealed spatially and transcriptomically-distinct mesenchymal zone-associated subclusters, including a quiescent undifferentiated progenitor-like subpopulation and clusters with characteristics of early and late stage EMT. Two early stage EMT clusters were distinguished by signatures of either myeloid cell interaction or hypoxia, and both were demonstrated to be EMT-initiating processes in in-vitro PFA experimental models. Myeloid cell interaction is the predominant initiating stage of EMT in PFA, occurring in zones that are spatially distinct from hypoxia induced EMT. Other mesenchymal clusters represent later EMT stages characterized by wound repair and tissue remodeling. Increased proliferation was a general characteristic of epithelial zone clusters, which included a second undifferentiated progenitor-like population that showed a particularly high mitotic rate and was associated with histologically hypercellular areas. Given the biological parallels with normal wound healing, we propose that mesenchymal and epithelial zones interact to create a cycle of persistent tissue damage response and mitogenic re-epithelialization signals. Unresolved wound repair is therefore a potential driver of PFA progression, a new concept that could provide novel targets for effective therapeutic intervention.