Cellular hierarchies of embryonal tumors with multilayered rosettes are shaped by oncogenic microRNAs and receptor-ligand interactions.

in Nature cancer by Alexander Beck, Lisa Gabler-Pamer, Gustavo Alencastro Veiga Cruzeiro, Sander Lambo, Bernhard Englinger, McKenzie L Shaw, Olivia A Hack, Ilon Liu, Rebecca D Haase, Carlos A O de Biagi, Alicia Baumgartner, Andrezza Do Nascimento Silva, Marbod Klenner, Pia S Freidel, Jochen Herms, Louisa von Baumgarten, Joerg C Tonn, Niklas Thon, Katharina Bruckner, Sibylle Madlener, Lisa Mayr, Daniel Senfter, Andreas Peyrl, Irene Slavc, Daniela Lötsch, Christian Dorfer, Rene Geyregger, Nicole Amberg, Christine Haberler, Norman Mack, Benjamin Schwalm, Stefan M Pfister, Andrey Korshunov, Lissa C Baird, Edward Yang, Susan N Chi, Sanda Alexandrescu, Johannes Gojo, Marcel Kool, Volker Hovestadt, Mariella G Filbin

TLDR

  • The study reveals the cellular hierarchy and C19MC activation in ETMR, identifying fibroblast growth factor receptor and Notch signaling as potential therapeutic targets.
  • The findings provide a powerful rationale for more effective targeted therapies in ETMR patients.
  • Future research directions aim to explore the feasibility of targeting these signaling pathways and characterizing the role of C19MC in ETMR pathobiology.

Abstract

Embryonal tumor with multilayered rosettes (ETMR) is a pediatric brain tumor with dismal prognosis. Characteristic alterations of the chromosome 19 microRNA cluster (C19MC) are observed in most ETMR; however, the ramifications of C19MC activation and the complex cellular architecture of ETMR remain understudied. Here we analyze 11 ETMR samples from patients using single-cell transcriptomics and multiplexed spatial imaging. We reveal a spatially distinct cellular hierarchy that spans highly proliferative neural stem-like cells and more differentiated neuron-like cells. C19MC is predominantly expressed in stem-like cells and controls a transcriptional network governing stemness and lineage commitment, as resolved by genome-wide analysis of microRNA-mRNA binding. Systematic analysis of receptor-ligand interactions between malignant cell types reveals fibroblast growth factor receptor and Notch signaling as oncogenic pathways that can be successfully targeted in preclinical models and in one patient with ETMR. Our study provides fundamental insights into ETMR pathobiology and a powerful rationale for more effective targeted therapies.

Overview

  • The study focuses on embryonal tumor with multilayered rosettes (ETMR), a pediatric brain tumor with dismal prognosis.
  • The researchers analyzed 11 ETMR samples using single-cell transcriptomics and multiplexed spatial imaging to understand the tumor's cellular architecture and C19MC activation.
  • The primary objective is to identify the ramifications of C19MC activation and potential therapeutic targets in ETMR.

Comparative Analysis & Findings

  • The study reveals a spatially distinct cellular hierarchy in ETMR, consisting of highly proliferative neural stem-like cells and more differentiated neuron-like cells.
  • C19MC is predominantly expressed in stem-like cells and controls a transcriptional network governing stemness and lineage commitment.
  • Systematic analysis of receptor-ligand interactions between malignant cell types identifies fibroblast growth factor receptor and Notch signaling as oncogenic pathways that can be targeted.

Implications and Future Directions

  • The study provides fundamental insights into ETMR pathobiology and a powerful rationale for more effective targeted therapies.
  • Future research directions include exploring the feasibility of targeting fibroblast growth factor receptor and Notch signaling in ETMR patients.
  • The study highlights the importance of further characterizing the role of C19MC in ETMR and identifying additional therapeutic targets.
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