Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1003904 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25592538_1.fastq.gz | Fastqsanger.gz | |||
| SRR25592538_2.fastq.gz | Fastqsanger.gz | |||
| SRR25592539_1.fastq.gz | Fastqsanger.gz | |||
| SRR25592539_2.fastq.gz | Fastqsanger.gz | |||
| SRR25592540_1.fastq.gz | Fastqsanger.gz |
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Project description:Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells
| PRJNA1003899 | ENA
Project description:Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. Here, we explore functional drivers of post-treatment recurrent GBM. By conducting genome-wide CRISPR-Cas9 knockout screens in patient-derived GBM models, we uncover distinct genetic dependencies in recurrent tumor cells absent in their patient-matched primary predecessors, accompanied by increased mutational burden and differential transcript and protein expression. These analyses map a multilayered genetic response to drive tumor recurrence, identifying protein tyrosine phosphatase 4A2 (PTP4A2) as a novel modulator of self-renewal, proliferation and tumorigenicity at GBM recurrence. Genetic perturbation or small molecule inhibition of PTP4A2 activity represses axon guidance activity through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1), exploiting a functional dependency on ROBO signaling. Importantly, engineered anti-ROBO1 single-domain antibodies mimic effects of PTP4A2 inhibition. Since a pan-PTP4A inhibitor was limited by poor penetrance across the blood brain barrier (BBB) in vivo, a second-generation chimeric antigen receptor (CAR)-T cell therapy was engineered against ROBO1 that elicits specific and potent anti-tumor responses in vivo. A single dose of anti-ROBO1 CAR-T cells doubles median survival in patient-derived xenograft (PDX) models of recurrent glioblastoma, and also eradicates tumors in ~50% of mice in PDX models of adult lung-to-brain metastases and pediatric relapsed medulloblastoma. We conclude that functional reprogramming drives tumorigenicity and dependence on a multi-targetable PTP4A-ROBO1 signaling axis at GBM recurrence, with potential in other malignant brain tumors.
2024-08-30 | GSE240490 | GEO
Project description:Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. Here, we explore functional drivers of post-treatment recurrent GBM. By conducting genome-wide CRISPR-Cas9 knockout screens in patient-derived GBM models, we uncover distinct genetic dependencies in recurrent tumor cells absent in their patient-matched primary predecessors, accompanied by increased mutational burden and differential transcript and protein expression. These analyses map a multilayered genetic response to drive tumor recurrence, identifying protein tyrosine phosphatase 4A2 (PTP4A2) as a novel modulator of self-renewal, proliferation and tumorigenicity at GBM recurrence. Genetic perturbation or small molecule inhibition of PTP4A2 activity represses axon guidance activity through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1), exploiting a functional dependency on ROBO signaling. Importantly, engineered anti-ROBO1 single-domain antibodies mimic effects of PTP4A2 inhibition. Since a pan-PTP4A inhibitor was limited by poor penetrance across the blood brain barrier (BBB) in vivo, a second-generation chimeric antigen receptor (CAR)-T cell therapy was engineered against ROBO1 that elicits specific and potent anti-tumor responses in vivo. A single dose of anti-ROBO1 CAR-T cells doubles median survival in patient-derived xenograft (PDX) models of recurrent glioblastoma, and also eradicates tumors in ~50% of mice in PDX models of adult lung-to-brain metastases and pediatric relapsed medulloblastoma. We conclude that functional reprogramming drives tumorigenicity and dependence on a multi-targetable PTP4A-ROBO1 signaling axis at GBM recurrence, with potential in other malignant brain tumors.
2024-08-07 | GSE240418 | GEO
Project description:Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells [Genome-wide CRISPR-Cas9]
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Project description:This SuperSeries is composed of the SubSeries listed below.
2024-08-10 | GSE240492 | GEO
Project description:Whole cell proteomics analysis of patient-matched glioblastoma models collected pre-treatment primary tumor (BT594) and post standard-of-care at first tumor recurrence (BT972).
2024-05-27 | MSV000094876 | MassIVE
Project description:The goal of the study was to compare gene expression of Robo1+/+ and Robo1-/- luminal progenitors. Total RNAs were then extracted from FACS purified luminal progenitor cells, harvested from Robo1+/+ or Robo1-/- mice (n=3 per genotype, two animals per n) using TRIreagent LS (Sigma, T3934). Poly(A)+ RNA sequencing libraries were made from each sample using the TruSeq RNA library preparation kit v.1 (Illumina). Illumina RNA PolyA library preparation guide. A total of 6 libraries were created by PCR amplification with Illumina barcoding primers using kit recommended conditions and quantified using a Bioanalyzer DNA 1000 kit (Agilent).
2021-10-12 | GSE164707 | GEO
Project description:Axon guidance is required for the establishment of brain circuits. Whether much of the molecular basis of axon guidance is known from animal models, the molecular machinery coordinating axon growth and pathfinding in humans remains to be elucidated. The use of induced pluripotent stem cells (iPSC) from human donors has revolutionized in vitro studies of the human brain. iPSC can be differentiated into neuronal stem cells which can be used to generate neural tissue-like cultures, known as neurospheres, that reproduce, in many aspects, the cell types and molecules present in the brain. Here, we analyzed quantitative changes in the proteome of neurospheres during differentiation. Relative quantification was performed at early time points during differentiation using iTRAQ-based labeling and LC-MS/MS analysis. We identified 6438 proteins, from which 433 were downregulated and 479 were upregulated during differentiation. We show that human neurospheres have a molecular profile that correlates to the fetal brain. During differentiation, upregulated pathways are related to neuronal development and differentiation, cell adhesion and axonal guidance whereas cell proliferation pathways were downregulated. We developed a functional assay to check for neurite outgrowth in neurospheres and confirmed that neurite outgrowth potential is increased after 10 days of differentiation and is enhanced by increasing cyclic AMP levels. The proteins identified here represent a resource to monitor neurosphere differentiation and coupled to the neurite outgrowth assay can be used to functionally explore neurological disorders using human neurospheres as a model.
2021-02-25 | PXD024177 | Pride
Project description:We previously identified inactivating mutations in roundabout guidance receptor 1 (ROBO1) in patients with myelodysplastic syndrome (MDS), which was associated with poor prognosis and susceptibility to acute myeloid leukemia (AML) transformation. Nonetheless, the exact role of ROBO1 in hematopoiesis remains poorly delineated. Here we report that the ablation of Robo1 in mice is sufficient to confer MDS-like disease with anemia and multilineage dysplasia. More specifically, Robo1 deficiency impairs the self-renewal and differentiation capacity of hematopoietic stem progenitor cells (HSPCs) and disrupts HSPC pool, especially the reduction of megakaryocyte erythroid progenitors (MEPs), which causes a blockage in the early stages of erythropoiesis in mice. Similarly, Robo1-deficienct HSPCs recapitulated MDS-like disease with anemia and multilineage dysplasia in transplanted mice. Correspondingly, clinical data also reveal that low expression of ROBO1 is associated with shortened survival, severe anemia and a high risk of AML transformation in patients with MDS. Mechanistically, transcriptional profiling indicates that Cdc42, a member of the Rho-GTPase family, serves as a downstream target gene for Robo1 in HSPCs. Overexpression of Cdc42 partially restores the proliferation of erythroid colonies in Robo1 deficient mice. In contrast, Cdc42 inhibitor (CASIN) effectively attenuates the erythroid colony formation of HSPCs. Collectively, our results suggest that Robo1 deficiency may provide a promising therapeutic target against MDS by impairing HSPC self-renewal and erythropoiesis via CDC42, predicting a poor prognosis for severe anemia and a high risk of AML transformation in MDS.
2023-12-01 | GSE231641 | GEO
Project description:RNA-seq of nulliparus Robo1+/+ and Robo1-/- luminal progenitors
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