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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Oct 08, 2021 |
| Title |
Glioblastoma Genetic Drivers Dictate the Function of Tumor-Associated Macrophages/Microglia and Responses to CSF1R Inhibition |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Tumor-associated macrophages/microglia (TAMs) are prominent microenvironment components in human glioblastoma (GBM) that are potential targets for anti-tumor therapy. However, TAM depletion by CSF1R inhibition showed mixed results in clinical trials. We hypothesized that GBM subtype-specific tumor microenvironment convey distinct sensitivities to TAM targeting.We generated syngeneic PDGFB-driven and RAS-driven GBM models that resemble proneural-like and mesenchymal-like gliomas, and determined the effect of TAM targeting by CSF1R inhibitor PLX3397 on glioma growth. We also investigated the co-targeting of TAMs and angiogenesis on PLX3397-resistant RAS-driven GBM. Using single-cell transcriptomic profiling, we further explored differences in tumor microenvironment cellular compositions and functions in PDGFB- and RAS-driven gliomas. We found that growth of PDGFB-driven tumors was markedly inhibited by PLX3397. In contrast, depletion of TAMs at the early phase accelerated RAS-driven tumor growth and had no effects on other proneural and mesenchymal GBM models. In addition, PLX3397-resistant RAS-driven tumors did not respond to PI3K signaling inhibition. Single-cell transcriptomic profiling revealed that PDGFB-driven gliomas induced expansion and activation of pro-tumor microglia, whereas TAMs in mesenchymal RAS-driven GBM were enriched in pro-inflammatory and angiogenic signaling. Co-targeting of TAMs and angiogenesis decreased cell proliferation and changed the morphology of RAS-driven gliomas.Our work identify functionally distinct TAM subpopulations in the growth of different glioma subtypes. Notably, we uncover a potential responsiveness of resistant mesenchymal-like gliomas to combined anti-angiogenic therapy and CSF1R inhibition. These data highlight the importance of characterization of the microenvironment landscape in order to optimally stratify patients for TAM-targeted therapy.
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| Overall design |
Single Cell RNA-seq (10X and Drop-Seq) for glioma driven by HRasV12 and dominant negative p53. Bulk RNA-seq of Ras-driven glioma tumor tissues from mouse treated with vehicle and PLX3397. Bulk RNA-seq of cell lines derived from PDGFB and Ras-driven GBM. Bulk RNA-seq of Cd11b+ positive cells from PDGFB-driven GBM after three days of vehicle or PLX3397 treatment
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| Contributor(s) |
Rao R, Han R, Ogurek S, Xue C, Wu LM, Zhang L, Zhang L, Hu J, Phoenix TN, Waggoner SN, Lu QR |
| Citation(s) |
34562087 |
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| Submission date |
Oct 06, 2021 |
| Last update date |
Jan 24, 2023 |
| Contact name |
Qing Richard Lu |
| E-mail(s) |
[email protected], [email protected]
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| Organization name |
Cincinnati Children's Hospital Medical Center
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| Street address |
3333 Burnet Ave
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| City |
Cincinnati |
| State/province |
OH |
| ZIP/Postal code |
45229 |
| Country |
USA |
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| Platforms (2) |
| GPL23479 |
BGISEQ-500 (Mus musculus) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (18)
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| Relations |
| BioProject |
PRJNA769082 |
| SRA |
SRP340398 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE185420_PDGFB_PLX3397_TAM_3days_counts.txt.gz |
167.4 Kb |
(ftp)(http) |
TXT |
| GSE185420_RAW.tar |
49.7 Mb |
(http)(custom) |
TAR (of MTX, TSV, TXT) |
| GSE185420_RasBulkTumor_VehvsPLX3397_Processed.txt.gz |
494.3 Kb |
(ftp)(http) |
TXT |
| GSE185420_Ras_PDGFRA_PDGFBCellLines_ProcessedData_Counts.txt.gz |
540.7 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
| Processed data provided as supplementary file |
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