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

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GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant
Cancer Cell ( IF 48.8 ) Pub Date : 2024-09-03 , DOI: 10.1016/j.ccell.2024.08.006
Ilon Liu ₁ , Gustavo Alencastro Veiga Cruzeiro ₂ , Lynn Bjerke ₃ , Rebecca F Rogers ₃ , Yura Grabovska ₃ , Alexander Beck ₄ , Alan Mackay ₃ , Tara Barron ₅ , Olivia A Hack ₂ , Michael A Quezada ₅ , Valeria Molinari ₃ , McKenzie L Shaw ₂ , Marta Perez-Somarriba ₆ , Sara Temelso ₃ , Florence Raynaud ₇ , Ruth Ruddle ₇ , Eshini Panditharatna ₂ , Bernhard Englinger ₈ , Hafsa M Mire ₂ , Li Jiang ₂ , Andrezza Nascimento ₂ , Jenna LaBelle ₂ , Rebecca Haase ₂ , Jacob Rozowsky ₂ , Sina Neyazi ₂ , Alicia-Christina Baumgartner ₂ , Sophia Castellani ₂ , Samantha E Hoffman ₂ , Amy Cameron ₉ , Murry Morrow ₉ , Quang-De Nguyen ₉ , Giulia Pericoli ₁₀ , Sibylle Madlener ₁₁ , Lisa Mayr ₁₁ , Christian Dorfer ₁₂ , Rene Geyeregger ₁₃ , Christopher Rota ₁₄ , Gerda Ricken ₁₅ , Keith L Ligon ₁₆ , Sanda Alexandrescu ₁₇ , Rodrigo T Cartaxo ₁₈ , Benison Lau ₁₈ , Santhosh Uphadhyaya ₁₈ , Carl Koschmann ₁₈ , Emelie Braun ₁₉ , Miri Danan-Gotthold ₁₉ , Lijuan Hu ₁₉ , Kimberly Siletti ₁₉ , Erik Sundström ₂₀ , Rebecca Hodge ₂₁ , Ed Lein ₂₁ , Sameer Agnihotri ₂₂ , David D Eisenstat ₂₃ , Simon Stapleton ₂₄ , Andrew King ₂₅ , Cristina Bleil ₂₆ , Angela Mastronuzzi ₁₀ , Kristina A Cole ₂₇ , Angela J Waanders ₂₈ , Angel Montero Carcaboso ₂₉ , Ulrich Schüller ₃₀ , Darren Hargrave ₃₁ , Maria Vinci ₁₀ , Fernando Carceller ₃₂ , Christine Haberler ₁₅ , Irene Slavc ₁₁ , Sten Linnarsson ₁₉ , Johannes Gojo ₃₃ , Michelle Monje ₃₄ , Chris Jones ₃ , Mariella G Filbin ₂

Affiliation

Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Neurology with Experimental Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin und Humboldt-Universität zu Berlin, 10117 Berlin, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Digital Clinician Scientist Program, 10117 Berlin, Germany.
Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Division of Molecular Pathology, The Institute of Cancer Research, Sutton, Surrey SM2 5 NG, UK.
Center for Neuropathology, Ludwig-Maximilians-University, 81377 Munich, Germany.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
Children & Young People's Unit, Royal Marsden Hospital NHS Trust, Sutton, Surrey SM2 5 NG, UK.
Division of Cancer Therapeutics, The Institute of Cancer Research, London SW7 3RK, UK.
Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Department of Onco-haematology, Gene and Cell Therapy, Bambino Gesù Children's Hospital-IRCCS, 00165 Rome, Italy.
Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
Department of Neurosurgery, Medical University of Vienna, 1090 Vienna, Austria.
Clinical Cell Biology, Children's Cancer Research Institute (CCRI), Vienna 1090, Austria.
Department of Neurobiology, Harvard Medical School, Boston, MA 02215, USA.
Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna 1090, Austria.
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA; Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
Department of Pathology, Boston Children's Hospital, Boston, MA 02115, USA.
Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden.
Division of Neurodegeneration, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, 17177 Stockholm, Sweden.
Allen Institute for Brain Science, Seattle, WA 98109, USA.
Departments of Neurosurgery and Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
Murdoch Children's Research Institute, Department of Paediatrics, University of Melbourne, Parkville, VIC 3052, Australia.
Department of Neurosurgery, St George's Hospital NHS Trust, London SW17 0QT, UK.
Department of Neuropathology, King's College Hospital NHS Trust, London SE5 9RS, UK.
Department of Neurosurgery, King's College Hospital NHS Trust, London SE5 9RS, UK.
Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
Laboratory of Molecular Oncology, Hospital Sant Joan de Déu, 08950 Barcelona, Spain.
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
University College London Great Ormond Street Institute for Child Health, London WC1N 1EH, UK.
Children & Young People's Unit, Royal Marsden Hospital NHS Trust, Sutton, Surrey SM2 5 NG, UK; Division of Clinical Studies, The Institute of Cancer Research, London SW7 3RK, UK.
Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA; Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford, CA, USA.

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.

中文翻译：

GABA能神经元谱系的发育决定了H3G34突变型弥漫性半球神经胶质瘤的临床可操作靶点

弥漫性半球胶质瘤 H3G34R/V 突变体 (DHG-H3G34) 是缺乏靶向治疗的致命脑肿瘤。它们起源于神经元间前体；然而，利用这一起源来获得治疗见解仍有待探索。在这里，我们沿着中间神经元谱系发育连续体描绘了一个细胞层次结构，揭示了 DHG-H3G34 反映了中间神经元巢周围祖细胞流的空间模式，如人脑发育过程中所见。将这些发现与全基因组 CRISPR-Cas9 筛选相结合，将中间神经元谱系祖细胞中上调的基因确定为主要依赖性。其中，CDK6 作为一个可靶向的脆弱性出现：DHG-H3G34 肿瘤细胞对 CDK4/6 抑制剂和 CDK6 特异性降解剂表现出增强的敏感性，促进向更成熟的中间神经元样状态的转变，减少肿瘤生长，并延长异种移植物存活。值得注意的是，一位患有进展性 DHG-H3G34 的患者接受 CDK4/6 抑制剂治疗后病情稳定了 17 个月。这项研究强调了在特征性生态位中组织的神经元间祖细胞样状态，这是 DHG-H3G34 中的一个明显的脆弱性，强调 CDK6 作为一个有前途的临床可行靶点。

更新日期：2024-09-03

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