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

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

doi:10.1016/j.ccell.2024.08.006

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

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 JiangAndrezza 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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.

Original language	English
Pages (from-to)	1528-1548.e17
Journal	Cancer Cell
Volume	42
Issue number	9
DOIs	https://doi.org/10.1016/j.ccell.2024.08.006
State	Published - 9 Sep 2024
Externally published	Yes

Funding

Funders	Funder number
Bonnie Feldman of National Brain Tumor Society
AMGEN
CHILDREN with CANCER UK
Billie Butterfly Fund
Great Ormond Street Hospital Charity
Cuming Family Fund for Pediatric Brain Tumor Research
Caroline Mortimer Fund for Pediatric Neuro-Oncology
Director’s New Innovator Award
Brain Tumour Charity
Hall-Hunter Foundation
Eli Lilly and Company
Charité – Universitätsmedizin Berlin
Helen Gurley Brown Foundation
Alex's Lemonade Stand Foundation for Childhood Cancer
Royal Marsden Cancer Charity
Sontag Foundation
Forschungsgesellschaft für zerebrale Tumore
Claudia Adams Barr Fund
Deutsche Krebshilfe
CRIS Cancer Foundation
Novartis Pharmaceuticals UK Limited
NIHR Great Ormond Street Hospital Biomedical Research Centre
Burroughs Wellcome Fund
British Microcirculation Society
Medizinische Universität Wien
Deutsche Forschungsgemeinschaft	EXC-2049 - 390688087, -3486/1-1, 3486/2-1
Berlin Institute of Health	T32CA272386-01A1
National Cancer Institute	2P50CA165962
DKH	70114214
National Institutes of Health	DP2NS127705
Austrian Science Fund	J-4311
Cancer Research UK	C13468/A23536, DRCRPG-Nov21∖100002

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2024.08.006

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Liu, I., Alencastro Veiga Cruzeiro, G., Bjerke, L., Rogers, R. F., Grabovska, Y., Beck, A., Mackay, A., Barron, T., Hack, O. A., Quezada, M. A., Molinari, V., Shaw, M. L., Perez-Somarriba, M., Temelso, S., Raynaud, F., Ruddle, R., Panditharatna, E., Englinger, B., Mire, H. M., ... Filbin, M. G. (2024). GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant. Cancer Cell, 42(9), 1528-1548.e17. https://doi.org/10.1016/j.ccell.2024.08.006

@article{d5fc9eaef49741b487ba9d2572b15871,

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

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.",

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

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = sep,

day = "9",

doi = "10.1016/j.ccell.2024.08.006",

language = "אנגלית",

volume = "42",

pages = "1528--1548.e17",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

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Liu, I, Alencastro Veiga Cruzeiro, G, Bjerke, L, Rogers, RF, Grabovska, Y, Beck, A, Mackay, A, Barron, T, Hack, OA, Quezada, MA, Molinari, V, Shaw, ML, Perez-Somarriba, M, Temelso, S, Raynaud, F, Ruddle, R, Panditharatna, E, Englinger, B, Mire, HM, Jiang, L, Nascimento, A, LaBelle, J, Haase, R, Rozowsky, J, Neyazi, S, Baumgartner, AC, Castellani, S, Hoffman, SE, Cameron, A, Morrow, M, Nguyen, QD, Pericoli, G, Madlener, S, Mayr, L, Dorfer, C, Geyeregger, R, Rota, C, Ricken, G, Ligon, KL, Alexandrescu, S, Cartaxo, RT, Lau, B, Uphadhyaya, S, Koschmann, C, Braun, E, Danan-Gotthold, M, Hu, L, Siletti, K, Sundström, E, Hodge, R, Lein, E, Agnihotri, S, Eisenstat, DD, Stapleton, S, King, A, Bleil, C, Mastronuzzi, A, Cole, KA, Waanders, AJ, Montero Carcaboso, A, Schüller, U, Hargrave, D, Vinci, M, Carceller, F, Haberler, C, Slavc, I, Linnarsson, S, Gojo, J, Monje, M, Jones, C & Filbin, MG 2024, 'GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant', Cancer Cell, vol. 42, no. 9, pp. 1528-1548.e17. https://doi.org/10.1016/j.ccell.2024.08.006

TY - JOUR

T1 - GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant

AU - Liu, Ilon

AU - Alencastro Veiga Cruzeiro, Gustavo

AU - Bjerke, Lynn

AU - Rogers, Rebecca F.

AU - Grabovska, Yura

AU - Beck, Alexander

AU - Mackay, Alan

AU - Barron, Tara

AU - Hack, Olivia A.

AU - Quezada, Michael A.

AU - Molinari, Valeria

AU - Shaw, McKenzie L.

AU - Perez-Somarriba, Marta

AU - Temelso, Sara

AU - Raynaud, Florence

AU - Ruddle, Ruth

AU - Panditharatna, Eshini

AU - Englinger, Bernhard

AU - Mire, Hafsa M.

AU - Jiang, Li

AU - Nascimento, Andrezza

AU - LaBelle, Jenna

AU - Haase, Rebecca

AU - Rozowsky, Jacob

AU - Neyazi, Sina

AU - Baumgartner, Alicia Christina

AU - Castellani, Sophia

AU - Hoffman, Samantha E.

AU - Cameron, Amy

AU - Morrow, Murry

AU - Nguyen, Quang De

AU - Pericoli, Giulia

AU - Madlener, Sibylle

AU - Mayr, Lisa

AU - Dorfer, Christian

AU - Geyeregger, Rene

AU - Rota, Christopher

AU - Ricken, Gerda

AU - Ligon, Keith L.

AU - Alexandrescu, Sanda

AU - Cartaxo, Rodrigo T.

AU - Lau, Benison

AU - Uphadhyaya, Santhosh

AU - Koschmann, Carl

AU - Braun, Emelie

AU - Danan-Gotthold, Miri

AU - Hu, Lijuan

AU - Siletti, Kimberly

AU - Sundström, Erik

AU - Hodge, Rebecca

AU - Lein, Ed

AU - Agnihotri, Sameer

AU - Eisenstat, David D.

AU - Stapleton, Simon

AU - King, Andrew

AU - Bleil, Cristina

AU - Mastronuzzi, Angela

AU - Cole, Kristina A.

AU - Waanders, Angela J.

AU - Montero Carcaboso, Angel

AU - Schüller, Ulrich

AU - Hargrave, Darren

AU - Vinci, Maria

AU - Carceller, Fernando

AU - Haberler, Christine

AU - Slavc, Irene

AU - Linnarsson, Sten

AU - Gojo, Johannes

AU - Monje, Michelle

AU - Jones, Chris

AU - Filbin, Mariella G.

PY - 2024/9/9

Y1 - 2024/9/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85207802850&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2024.08.006

DO - 10.1016/j.ccell.2024.08.006

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C2 - 39232581

AN - SCOPUS:85207802850

SN - 1535-6108

VL - 42

SP - 1528-1548.e17

JO - Cancer Cell

JF - Cancer Cell

IS - 9

ER -

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

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UN SDGs

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