Dataset Information

Phosphoproteomic analysis in Glioblastoma in response to AZD1775

ABSTRACT: The aim of this study was to characterize phosphoproteome in response to AZD1775 in patient derived xenografts (PDX) lines and clinical specimens in glioblastoma. Tyrosine and motif specific serine and threonine phosphorylation were measured using quantitative LC-MS/MS based on TMT labeling.

INSTRUMENT(S): Q Exactive HF, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Brain Glioblastoma Multiforme

SUBMITTER: Ishwar Kohale

LAB HEAD: Forest Michael White

PROVIDER: PXD018782 | Pride | 2022-10-13

REPOSITORIES: Pride

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Publications

Multimodal platform for assessing drug distribution and response in clinical trials.

Lopez Begoña G C BGC Kohale Ishwar N IN Du Ziming Z Korsunsky Ilya I Abdelmoula Walid M WM Dai Yang Y Stopka Sylwia A SA Gaglia Giorgio G Randall Elizabeth C EC Regan Michael S MS Basu Sankha S SS Clark Amanda R AR Marin Bianca-Maria BM Mladek Ann C AC Burgenske Danielle M DM Agar Jeffrey N JN Supko Jeffrey G JG Grossman Stuart A SA Nabors Louis B LB Raychaudhuri Soumya S Ligon Keith L KL Wen Patrick Y PY Alexander Brian B Lee Eudocia Q EQ Santagata Sandro S Sarkaria Jann J White Forest M FM Agar Nathalie Y R NYR

Neuro-oncology 20220101 1

<h4>Background</h4>Response to targeted therapy varies between patients for largely unknown reasons. Here, we developed and applied an integrative platform using mass spectrometry imaging (MSI), phosphoproteomics, and multiplexed tissue imaging for mapping drug distribution, target engagement, and adaptive response to gain insights into heterogeneous response to therapy.<h4>Methods</h4>Patient-derived xenograft (PDX) lines of glioblastoma were treated with adavosertib, a Wee1 inhibitor, and tiss ...[more]

PMID: 34383057

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Project description:The role of YAP (Yes associated protein 1 gene) and MRTF-A (Megakaryoblastic Leukemia gene, MLK1), two transcriptional co-activators regulated downstream of GPCRs (G-protein coupled receptor) and RhoA, in growth of glioblastoma cells and in vivo GBM tumor development was explored using human glioblastoma cell lines (1321N1) and tumor initiating cells derived from patient derived xenografts (PDX)PDX (GSC-23) cells. Knockdown of these co-activators in PDX cells using shRNA significantly attenuated in vitro proliferation and stemness assessed by limiting dilution and neurosphere formation. Orthotopic xenografts of the MRTF-A and YAP knockdown PDX cells formed significantly smaller tumors with lower morbidity than wild-type cells. In vitro studies of cellular responses to the GPCR agonist sphingosine 1-phosphate (S1P) demonstrated that YAP was required for glioblastoma cell invasion and migration, whereas MRTF-A, was required for cell adhesion. S1P- stimulated proliferation was abolished by knockout of either YAP or MRTF-A. Gene expression analysis by RNA-sequencing of S1P- treated 1321N1 cells in which MRTF-A and or YAP were deleted knockout cells identified 44 genes that were induced through RhoA and highly dependent on YAP, MRTF-A, or both. Knockdown of F3 (tissue factor; TF), a target gene regulated selectively through YAP, when knocked down blocked 1321N1 cell invasion and migration, whereas knockdown of HBEGF (Hheparin binding EGF-like growth factor) (HBEGF), a gene selectively induced through MRTF-A, prevented cell adhesion in response to S1P. Proliferation was sensitive to knockdown of several target genes dually regulated through both YAP and MRTF-A (CCN1 and MYC) or of those regulated by either factor. Expression of these same genes was decreased in tumors from PDX cells lacking YAP or MRTF-A, indicating that these transcriptional pathways are regulated in the in vivo GBM tumor environment and suggesting that their activation through GPCRs and RhoA contributes to growth and maintenance of human GBM.

Dataset Information

Phosphoproteomic analysis in Glioblastoma in response to AZD1775

Publications

Multimodal platform for assessing drug distribution and response in clinical trials.

Similar Datasets

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