EPCO-27. SINGLE-CELL ANALYSIS OF ETMR PATIENT SAMPLES LINKS TRANSCRIPTIONAL PHENOTYPES TO GENETIC DRIVER ALTERATIONS AND INFORMS NOVEL THERAPEUTIC STRATEGIES

Autor: Mariella G. Filbin, Sander Lambo, Bernhard Englinger, Olivia A Hack, Sibylle Madlener, Volker Hovestadt, McKenzie Shaw, Marcel Kool, Johannes Gojo, Stefan M. Pfister, Alexander M. Beck, Sanda Alexandrescu
Rok vydání: 2021
Předmět:
Zdroj: Neuro-Oncology. 23:vi7-vi8
ISSN: 1523-5866
1522-8517
DOI: 10.1093/neuonc/noab196.026
Popis: Embryonal tumor with multilayered rosettes (ETMR) is a malignant brain tumor that typically occurs in children under the age of three. Most patients die within two years of diagnosis, and more effective, targeted therapies are urgently needed. To better characterize the oncogenic mechanisms of key driver alterations and identify novel therapeutic targets, we studied the cellular heterogeneity of ETMR using single-cell RNA sequencing. Analyses conducted on >3,000 high-quality cells collected from ten primary and relapse specimens revealed a common cellular hierarchy across all tumors: A highly proliferative neural stem cell-like population (SOX2+) gives rise to intermediate progenitors (ASCL1+) and more differentiated neuron-like cells (STMN2/4+). These malignant populations closely match histological patterns of ETMR (i.e. rosettes, neuropil), as observed by immunofluorescence microscopy. Comparison to single-cell datasets from human embryos indicates resemblance to cell populations of the developing brain, but also reveals key ETMR-specific differences, including expression of the chromosome 19 miRNA cluster (C19MC, the presumed genetic driver of most ETMRs), which is restricted to the stem cell-like population. We next investigated if targeting C19MC is a viable strategy to disrupt the cellular hierarchy of ETMR. Silencing with antisense oligonucleotides shows pronounced reduction of cell line growth for a specific subset of the 46 members of C19MC. These miRNAs share seed sequences with evolutionary conserved miRNAs that have been shown to regulate pluripotency and self-renewal of embryonic stem cells. We hypothesize that select C19MC members play similar roles in ETMR and represent bona fide targets for therapeutic targeting using antisense technology.
Databáze: OpenAIRE
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