ETMR-17. SINGLE-CELL TRANSCRIPTOME ANALYSIS OF ETMR PATIENT SAMPLES. (4th December 2020)

• Record Type: Journal Article
• Authors: Hovestadt, Volker; Shaw, McKenzie L; Beck, Alexander; Lambo, Sander; Hack, Olivia A; Gojo, Johannes; Madlener, Sibylle; Mayr, Lisa; Haberler, Christine; Czech, Thomas; Hanson, Derek R; Koschmann, Carl; Jabado, Nada; Huang, Annie A; Slavc, Irene; Pfister, Stefan M; Alexandrescu, Sanda; Bernstein, Bradley E; Kool, Marcel; Filbin, Mariella G
• Is Part Of: Neuro-oncology. Volume 22(2020)Supplement 3
• Page Start: iii326
• Page End: iii326
• Publication Date: 2020-12-04
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noaa222.220
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Brain tumors are comprised of cells with heterogeneous genetic and transcriptional states, resulting in substantial phenotypic diversity. This diversity is particularly evident in embryonal tumor with multilayered rosettes (ETMR), which shows a striking bi-phasic pattern for which it is named. A better understanding of its underlying molecular makeup is urgently needed to develop more effective therapeutic strategies that eliminate all malignant cell types underlying ETMR initiation, maintenance, progression, and relapse. Furthermore, the cellular origin of ETMR is currently poorly understood. We used plate-based single-cell RNA sequencing to assess the intratumoral heterogeneity in 6 fresh and 4 snap-frozen surgical biopsies, following a workflow that we have previously established to study pediatric high grade gliomas, medulloblastomas, and ependymomas. Computational analyses conducted on >4, 000 single cells identified cellular hierarchies ranging from a proliferative, undifferentiated cell population to more differentiated, predominantly neural-like progeny in all samples. Patient-derived cell line and xenograft models partially recapitulated this hierarchy. We further integrated transcriptional programs identified in single cells with available datasets of the developing normal brain, as well as with programs identified in other pediatric brain tumor entities, to inform both putative cellular origins and ETMR-specific oncogenic pathways. These timely results provide unparalleled insights into the molecular underpinnings of the phenotypic heterogeneity observed in ETMR. Analyses aimed at further integrating malignant cell type abundances with genetic alterations and clinical annotations, and therapeutical targeting of malignant cell populations using in-vitro models are currently ongoing.