Abstract 154: Diffuse midline glioma invasion and metastasis rely on cell-autonomous signaling through a phenotypic switch controlled by BMP7

Abstract Diffuse midline gliomas (DMG) are pediatric tumors with negligible two-year survival after diagnosis characterized by their ability to infiltrate the central nervous system. In the hope of controlling the local growth and slowing the disease all patients receive radiotherapy. However, distant progression occurs frequently in DMG patients. Current clues as to what causes tumor infiltration circle mainly around the tumor microenvironment, but there are currently no known determinants to predict the degree of invasiveness. We use patient-derived glioma stem cells (GSCs) to create patient-specific 3D avatars to model interindividual invasion and elucidate the cellular supporting mechanisms. We show that 3D models mirror the invasive behavior of the parental tumors, thus proving the ability of DMG to infiltrate as an autonomous characteristic of tumor cells. Furthermore, we distinguished two modes of migration, mesenchymal and amoeboid-like, and associated the amoeboid-like modality with GSCs derived from the most invasive tumors. Using transcriptomics of both organoids and primary tumors, we further characterized the invasive amoeboid-like tumors as oligodendrocyte progenitor-like, with highly contractile cytoskeleton and reduced adhesion ability. Moreover, we identified the cell-autonomous BMP7-related signaling as a major regulator of DMG motility and invasion, controlling a switch between two migration modalities. Finally, we deciphered MEK, ERK and Rho/ROCK kinases activated downstream of the BMP7 stimulation as actionable targets controlling tumor cell motility. Our findings identify two new therapeutic avenues. First, patient-derived GSCs represent a predictive tool for stratification of patient with increased risk of metastatic progression in order to adapt their irradiation strategies within weeks after diagnosis. Second, autocrine and short-range BMP7-related signaling becomes a druggable target to prevent DMG spread and metastasis. Citation Format: Marco Bruschi, Lilia Midjek, Yassine Ajlil, Stephanie Vairy, Manon Lancien, Samia Ghermaoui, Thomas Kergrohen, Maite Verreault, Ahmed Idbaih, Carlos Alberto Oliveira de Biagi, Ilon Liu, Mariella G. Filbin, Kevin Beccaria, Thomas Blauwblomme, Stephanie Puget, Arnault Tauziede-Espariat, Pascale Varlet, Volodia Dangouloff-Ros, Nathalie Boddaert, Gwenael Le Teuff, Jacques Grill, Guillaume Montagnac, Nadia Elkathib, Marie-Anne Debily, David Castel. Diffuse midline glioma invasion and metastasis rely on cell-autonomous signaling through a phenotypic switch controlled by BMP7 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 154.