GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant.

in Cancer cell by Ilon Liu, Gustavo Alencastro Veiga Cruzeiro, Lynn Bjerke, Rebecca F Rogers, Yura Grabovska, Alexander Beck, Alan Mackay, Tara Barron, Olivia A Hack, Michael A Quezada, Valeria Molinari, McKenzie L Shaw, Marta Perez-Somarriba, Sara Temelso, Florence Raynaud, Ruth Ruddle, Eshini Panditharatna, Bernhard Englinger, Hafsa M Mire, Li Jiang, Andrezza Nascimento, Jenna LaBelle, Rebecca Haase, Jacob Rozowsky, Sina Neyazi, Alicia-Christina Baumgartner, Sophia Castellani, Samantha E Hoffman, Amy Cameron, Murry Morrow, Quang-De Nguyen, Giulia Pericoli, Sibylle Madlener, Lisa Mayr, Christian Dorfer, Rene Geyeregger, Christopher Rota, Gerda Ricken, Keith L Ligon, Sanda Alexandrescu, Rodrigo T Cartaxo, Benison Lau, Santhosh Uphadhyaya, Carl Koschmann, Emelie Braun, Miri Danan-Gotthold, Lijuan Hu, Kimberly Siletti, Erik Sundström, Rebecca Hodge, Ed Lein, Sameer Agnihotri, David D Eisenstat, Simon Stapleton, Andrew King, Cristina Bleil, Angela Mastronuzzi, Kristina A Cole, Angela J Waanders, Angel Montero Carcaboso, Ulrich Schüller, Darren Hargrave, Maria Vinci, Fernando Carceller, Christine Haberler, Irene Slavc, Sten Linnarsson, Johannes Gojo, Michelle Monje, Chris Jones, Mariella G Filbin

TLDR

  • The study found that a type of brain tumor called diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), lack targeted therapies and originate from interneuronal precursors. The study looked at how these tumors develop and found that they have a specific pattern of cells that are similar to interneurons in the human brain. The study then used a tool called CRISPR-Cas9 to find genes that are important for these interneuron-like cells to survive. The study found that one of these genes, called CDK6, is a target that can be used to treat DHG-H3G34. The study also found that these interneuron-like cells are organized in specific areas in the brain, which could be used to target them with treatments. The study highlights the importance of understanding how these tumors develop and finding ways to treat them.

Abstract

Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are lethal brain tumors lacking targeted therapies. They originate from interneuronal precursors; however, leveraging this origin for therapeutic insights remains unexplored. Here, we delineate a cellular hierarchy along the interneuron lineage development continuum, revealing that DHG-H3G34 mirror spatial patterns of progenitor streams surrounding interneuron nests, as seen during human brain development. Integrating these findings with genome-wide CRISPR-Cas9 screens identifies genes upregulated in interneuron lineage progenitors as major dependencies. Among these, CDK6 emerges as a targetable vulnerability: DHG-H3G34 tumor cells show enhanced sensitivity to CDK4/6 inhibitors and a CDK6-specific degrader, promoting a shift toward more mature interneuron-like states, reducing tumor growth, and prolonging xenograft survival. Notably, a patient with progressive DHG-H3G34 treated with a CDK4/6 inhibitor achieved 17 months of stable disease. This study underscores interneuronal progenitor-like states, organized in characteristic niches, as a distinct vulnerability in DHG-H3G34, highlighting CDK6 as a promising clinically actionable target.

Overview

  • The study focuses on diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), which lack targeted therapies and originate from interneuronal precursors. The study aims to delineate a cellular hierarchy along the interneuron lineage development continuum and identify genes upregulated in interneuron lineage progenitors as major dependencies. The primary objective is to identify a targetable vulnerability in DHG-H3G34, which can be exploited for therapeutic purposes. The study uses genome-wide CRISPR-Cas9 screens to identify genes upregulated in interneuron lineage progenitors as major dependencies. The study identifies CDK6 as a targetable vulnerability in DHG-H3G34, which can be exploited for therapeutic purposes. The study highlights interneuronal progenitor-like states, organized in characteristic niches, as a distinct vulnerability in DHG-H3G34, which can be exploited for therapeutic purposes.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions detailed in the study. The study identifies genes upregulated in interneuron lineage progenitors as major dependencies. The study identifies CDK6 as a targetable vulnerability in DHG-H3G34, which can be exploited for therapeutic purposes. The study highlights interneuronal progenitor-like states, organized in characteristic niches, as a distinct vulnerability in DHG-H3G34, which can be exploited for therapeutic purposes.

Implications and Future Directions

  • The study's findings highlight interneuronal progenitor-like states, organized in characteristic niches, as a distinct vulnerability in DHG-H3G34, which can be exploited for therapeutic purposes. The study identifies CDK6 as a targetable vulnerability in DHG-H3G34, which can be exploited for therapeutic purposes. The study underscores the importance of leveraging the origin of DHG-H3G34 for therapeutic insights. The study suggests that future research should focus on identifying additional targetable vulnerabilities in DHG-H3G34 and developing novel therapies based on these vulnerabilities. The study also suggests that future research should focus on identifying additional targetable vulnerabilities in DHG-H3G34 and developing novel therapies based on these vulnerabilities.
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