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Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240492 | GEO | 2024/08/10

REPOSITORIES: GEO

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Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells

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

Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR-T cells

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

Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells [Genome-wide CRISPR-Cas9]

2024-08-07 | GSE240418 | GEO

Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells

Project description:Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells

| PRJNA1003904 | ENA

Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells

Project description:Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells

| PRJNA1003899 | ENA

Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells [Genome-wide CRISPR-Cas9]

Project description:Targeting axonal guidance dependencies in glioblastoma with ROBO1 CAR T cells [Genome-wide CRISPR-Cas9]

| PRJNA1003542 | ENA

Targeting transcriptional dependencies in cancer using a covalent CDK7 inhibitor

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-12-23 | E-GEOD-50625 | biostudies-arrayexpress

Targeting transcriptional dependencies in cancer using a covalent CDK7 inhibitor

Project description:This SuperSeries is composed of the SubSeries listed below.

2013-12-23 | GSE50625 | GEO

Glioblastoma Stem Cells Reprogram Chromatin In Vivo To Generate Selective Therapeutic Dependencies

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-10-17 | GSE185956 | GEO

The lhx2 transcription factor controls thalamocortical axonal guidance by specific regulation of robo1 and robo2 receptors.

Project description:The assembly of neural circuits is dependent upon the generation of specific neuronal subtypes, each subtype displaying unique properties that direct the formation of selective connections with appropriate target cells. Actions of transcription factors in neural progenitors and postmitotic cells are key regulators in this process. LIM-homeodomain transcription factors control crucial aspects of neuronal differentiation, including subtype identity and axon guidance. Nonetheless, their regulation during development is poorly understood and the identity of the downstream molecular effectors of their activity remains largely unknown. Here, we demonstrate that the Lhx2 transcription factor is dynamically regulated in distinct pools of thalamic neurons during the development of thalamocortical connectivity in mice. Indeed, overexpression of Lhx2 provokes defective thalamocortical axon guidance in vivo, while specific conditional deletion of Lhx2 in the thalamus produces topographic defects that alter projections from the medial geniculate nucleus and from the caudal ventrobasal nucleus in particular. Moreover, we demonstrate that Lhx2 influences axon guidance and the topographical sorting of axons by regulating the expression of Robo1 and Robo2 guidance receptors, which are essential for these axons to establish correct connections in the cerebral cortex. Finally, augmenting Robo1 function restores normal axon guidance in Lhx2-overexpressing neurons. By regulating axon guidance receptors, such as Robo1 and Robo2, Lhx2 differentially regulates the axon guidance program of distinct populations of thalamic neurons, thus enabling the establishment of specific neural connections.

| S-EPMC6622047 | biostudies-literature

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