ETMR stem-like state and chemo-resistance are supported by perivascular cells at single-cell resolution
Abstract
Abstract Embryonal tumor with multilayered rosettes (ETMR) is a lethal embryonal brain tumor entity. To investigate the intratumoral heterogeneity and cellular communication in the tumor microenvironment (TME), we analyze in this work single-cell RNA sequencing of about 250,000 cells of primary human and murine ETMR, in vitro cultures, and a 3D forebrain organoid model of ETMR, supporting the main findings with immunohistochemistry and spatial transcriptomics of human tumors. We characterize three distinct malignant ETMR subpopulations - RG-like, NProg-like and NB-like - positioned within a putative neurodevelopmental hierarchy. We reveal PDGFRβ+ pericytes as key communication partners in the TME, contributing to stem cell signaling through extracellular matrix-mediated interactions with tumor cells. PDGF signaling is upregulated in chemoresistant RG-like cells in vivo and plays a role in recruiting pericytes to ETMR TME by finalizing a signaling cascade which promotes the differentiation of non-malignant radial glia cells, derived from our 3D model, into pericyte-like cells. Selective PDGFR-inhibition blocked the lineage differentiation into pericytes in vitro and reduced the tumor cell population in vivo. Targeting ETMR-pericyte interactions in the TME presents a promising therapeutic approach.
Article Details
Authors (39)
Flavia W. de Faria
Nicole C. Riedel
Daniel Münter
Marta Interlandi
Carolin Göbel
Lea Altendorf
Mathis Richter
Viktoria Melcher
Christian Thomas
Rajanya Roy
Melanie Schoof
Ivan Bedzhov
Natalia Moreno
Monika Graf
Marc Hotfilder
Dörthe Holdhof
Wolfgang Hartmann
Ann-Katrin Bruns
Angela Brentrup
Friederike Liesche-Starnecker
Bruno Maerkl
Sarah Sandmann
Julian Varghese
Martin Dugas
Pedro H. Pinto
Sebastian T. Balbach
I-Na Lu
Claudia Rossig
Oliver Soehnlein
Aysegül Canak
Martin Ebinger
Martin Schuhmann
Jens Schittenhelm
Michael F. Frühwald
Ulrich Schüller
Thomas K. Albert
Carolin Walter
Jan M. Bruder
Kornelius Kerl