 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Aug 01, 2024 |
| Title |
GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant [ChIP-Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are uniformly lethal malignancies lacking targeted therapies. These gliomas uniquely originate from interneuronal precursor cells, and leveraging this interneuronal lineage origin for mechanistic and therapeutic insights is a pressing need. Here, we elucidate the cell state composition of DHG-H3G34, resolving a cellular hierarchy along continuous interneuron lineage development. In the developing human brain, interneuron lineage precursors form characteristic histological patterns organized in streams of progenitor cells surrounding nests of migratory interneurons, and we find these same spatial patterns to be mirrored in primary DHG-H3G34 tumors. We integrated these findings with genome-wide CRISPR-Cas9 screens, which revealed the majority of dependencies to be genes upregulated in interneuron lineage progenitors, highlighting these as a driver of DHG-H3G34. We validated the essentiality of these lineage-associated targets in patient-derived in vitro and in vivo models. Among these, CDK6 emerged as a targetable dependency, and we demonstrated enhanced sensitivity of DHG-H3G34 tumor cells to CDK4/6 inhibitors and a CDK6-specific degrader. Inhibition of CDK6 shifted cells towards more mature interneuron-like cell states, reduced tumor growth, and prolonged survival of patient-derived xenografts. Concordantly, a patient with progressive DHG-H3G34 under second line therapy was treated with a CDK4/6 inhibitor, and exhibited stable disease for 17 months. Collectively, we identify interneuronal progenitor-like states, organized in characteristic developmental spatial niches, as a distinct vulnerability consistently upregulated in DHG-H3G34 tumors, and provide initial evidence for CDK6 as a clinically actionable target particularly relevant for its interneuronal developmental biology.
|
| |
|
| Overall design |
Ch-IP sequencing of of DHG-G34 patient derived glioma cells
|
| |
|
| Contributor(s) |
Liu I, Alencastro Veiga Cruzeiro G, Bjerke L, Rogers RF, Grabovska Y, Mackay A, Jones C, Filbin MG |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| |
| Submission date |
Jul 15, 2024 |
| Last update date |
Aug 01, 2024 |
| Contact name |
Chris Jones Jones |
| E-mail(s) |
chris.jones@icr.ac.uk
|
| Phone |
+4420834376171
|
| Organization name |
Institute of Cancer Research
|
| Department |
Molecular Pathology
|
| Lab |
Glioma Team
|
| Street address |
15 Cotswold Road
|
| City |
Sutton |
| State/province |
Surrey |
| ZIP/Postal code |
SM2 5NG |
| Country |
United Kingdom |
| |
|
| Platforms (1) |
|
| Samples (45)
|
|
| Relations |
| BioProject |
PRJNA1135967 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE272262_RAW.tar |
4.9 Gb |
(http)(custom) |
TAR (of BW) |
SRA Run Selector |
| Raw data are available in SRA |
|
|
|
|
 |
Less...
More...