Effects of targeting endothelial mTORC1 on metastatic tumor cells
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ABSTRACT:
PROVIDER: PRJNA1079804 | ENA |
REPOSITORIES: ENA
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Project description:Tumor metastasis, the main cause of death in cancer patients, requires outgrowth of tumor cells after their dissemination and residence in microscopic niches. Nutrient sufficiency is a determinant of such outgrowth. Fatty acids (FA) can be metabolized by cancer cells for their energetic and anabolic needs, thereby supporting metastatic progression. The vascular endothelium serves as a barrier to access of molecules into tissues, but it is unclear how fatty acid delivery to early metastatic tumors is regulated. Using a mouse model of metastatic outgrowth in the lung, we show that tumor endothelium actively promotes tumor growth by transferring FA into developing metastatic tumors. Tumor burden was significantly reduced upon endothelial-specific targeted deletion of Raptor, a unique component of the mTORC1 complex (RptorECKO). The goal of this study was to investigate how endothelial mTORC1 alters metastatic tumor cells.
2024-04-01 | GSE256508 | GEO
Project description:Tumor metastasis, the main cause of death in cancer patients, requires outgrowth of tumor cells after their dissemination and residence in microscopic niches. Nutrient sufficiency is a determinant of such outgrowth. Fatty acids (FA) can be metabolized by cancer cells for their energetic and anabolic needs, thereby supporting metastatic progression. The vascular endothelium serves as a barrier to access of molecules into tissues, but it is unclear how fatty acid delivery to early metastatic tumors is regulated. Using a mouse model of metastatic outgrowth in the lung, we show that tumor endothelium actively promotes tumor growth by transferring FA into developing metastatic tumors. Tumor burden was significantly reduced upon endothelial-specific targeted deletion of Raptor, a unique component of the mTORC1 complex (RptorECKO). The goal of this study was to investigate how targeting Raptor/mTORC1 impacts endothelial cells.
2024-04-01 | GSE256509 | GEO
Project description:Transcriptome changes associated with targeting mTORC1 in endothelial cells
| PRJNA1079803 | ENA
Project description:Acquired BRAF/MEK inhibitor resistance in melanoma results in a new transcriptional state associated with increased risk of metastasis. Here, we identified non-canonical EphA2 signaling as a driver of the resistance-associated metastatic state. We used mass spectrometry-based proteomic and phenotypic assays to demonstrate that the expression of active non-canonical EphA2-S897E in melanoma cells led to a mesenchymal-to-amoeboid transition (MAT) driven by Cdc42 activation. The induction of MAT promoted melanoma cell invasion, survival under shear stress, adhesion to endothelial cells under continuous flow conditions, increased permeability of endothelial cell monolayers and stimulated melanoma transendothelial cell migration. In vivo, melanoma cells expressing EphA2-S897E or active Cdc42 showed superior lung retention following tail-vain injection. Analysis of BRAF inhibitor-sensitive and -resistant melanoma cells demonstrated resistance to be associated with an MAT switch, upregulation of Cdc42 activity, increased invasion, and transendothelial migration. The drug resistant metastatic state was dependent upon histone deacetylase 8 (HDAC8) activity. Silencing of HDAC8 lead to inhibition of EphA2 and AKT phosphorylation, reduced invasion and impaired melanoma cell-endothelial cell interactions. In summary, we have demonstrated that the metastatic state associated with acquired BRAF inhibitor resistance is dependent on non-canonical EphA2 signaling, leading to increased melanoma-endothelial cell interactions and enhanced tumor dissemination.
2020-11-18 | PXD020250 | Pride
Project description:Acquired BRAF/MEK inhibitor resistance in melanoma results in a new transcriptional state associated with increased risk of metastasis. Here, we identified non-canonical EphA2 signaling as a driver of the resistance-associated metastatic state. We used mass spectrometry-based proteomic and phenotypic assays to demonstrate that the expression of active non-canonical EphA2-S897E in melanoma cells led to a mesenchymal-to-amoeboid transition (MAT) driven by Cdc42 activation. The induction of MAT promoted melanoma cell invasion, survival under shear stress, adhesion to endothelial cells under continuous flow conditions, increased permeability of endothelial cell monolayers and stimulated melanoma transendothelial cell migration. In vivo, melanoma cells expressing EphA2-S897E or active Cdc42 showed superior lung retention following tail-vain injection. Analysis of BRAF inhibitor-sensitive and -resistant melanoma cells demonstrated resistance to be associated with an MAT switch, upregulation of Cdc42 activity, increased invasion, and transendothelial migration. The drug resistant metastatic state was dependent upon histone deacetylase 8 (HDAC8) activity. Silencing of HDAC8 lead to inhibition of EphA2 and AKT phosphorylation, reduced invasion and impaired melanoma cell-endothelial cell interactions. In summary, we have demonstrated that the metastatic state associated with acquired BRAF inhibitor resistance is dependent on non-canonical EphA2 signaling, leading to increased melanoma-endothelial cell interactions and enhanced tumor dissemination.
2020-11-18 | PXD020241 | Pride
Project description:Acquired BRAF/MEK inhibitor resistance in melanoma results in a new transcriptional state associated with increased risk of metastasis. Here, we identified non-canonical EphA2 signaling as a driver of the resistance-associated metastatic state. We used mass spectrometry-based proteomic and phenotypic assays to demonstrate that the expression of active non-canonical EphA2-S897E in melanoma cells led to a mesenchymal-to-amoeboid transition (MAT) driven by Cdc42 activation. The induction of MAT promoted melanoma cell invasion, survival under shear stress, adhesion to endothelial cells under continuous flow conditions, increased permeability of endothelial cell monolayers and stimulated melanoma transendothelial cell migration. In vivo, melanoma cells expressing EphA2-S897E or active Cdc42 showed superior lung retention following tail-vain injection. Analysis of BRAF inhibitor-sensitive and -resistant melanoma cells demonstrated resistance to be associated with an MAT switch, upregulation of Cdc42 activity, increased invasion, and transendothelial migration. The drug resistant metastatic state was dependent upon histone deacetylase 8 (HDAC8) activity. Silencing of HDAC8 lead to inhibition of EphA2 and AKT phosphorylation, reduced invasion and impaired melanoma cell-endothelial cell interactions. In summary, we have demonstrated that the metastatic state associated with acquired BRAF inhibitor resistance is dependent on non-canonical EphA2 signaling, leading to increased melanoma-endothelial cell interactions and enhanced tumor dissemination.
2020-11-18 | PXD020242 | Pride
Project description:In the past decade, the relevance of tumor-induced lymphangiogenesis for the metastatic spread of tumor cells has been demonstrated, thus indicating the potential of targeting tumor lymphangiogenesis to treat cancer. Whereas numerous preclinical studies demonstrated that blocking angiogenesis or lymphangiogenesis could inhibit tumor metastasis, the scarcity of highly selective targeting candidates hampers their translation to the clinic. We employed a new approach consisting of immuno-laser capture microdissection (i-LCM) and transcriptional profiling by means of microarrays in order to identify novel tumor-specific endothelial markers. By using short immunostainings prior to microdissection, specific identification of lymphatic (LECs) and blood (BECs) endothelial cells was allowed. For the subsequent gene expression profiling, a single round of the Ribo-Spia amplification method in combination with the Affymterix microarray platform was used. Comparison of gene expression profiles of tumor-associated and normal LECs resulted in the identification of differentially expressed genes in tumor-associated lymphatic vasculature.
2010-04-12 | E-GEOD-15760 | biostudies-arrayexpress
Project description:Cerebral vascular malformations (CCM) are primarily found within brain, where they result in increased risk for stroke, seizures and focal neurological deficits. The unique feature of the brain vasculature is the blood-brain barrier (BBB) formed by the brain neurovascular unit, and recent studies suggest that loss of CCM genes causes disruptions of BBB integrity as the inciting event for the development of CCM. CCM lesion is proposed to be initially derived from a single clonal expansion of a subset of angiogenic venous capillary endothelial cells (ECs) and respective resident endothelial progenitor cells (EPCs). However, the critical signaling in the subclass of brain EC/EPC for the CCM lesion initiation and progression are unclear. Here we employed single-cell RNA-sequencing (scRNA-seq) analyses in early stages of the brain EC-specific Ccm3 deletion (Pdcd10BECKO) microvessels and identified a unique EPC cluster with high stem cell markers but low BBB-associated genes. mTORC1, but not mTORC2, is activated in mouse and human CCM lesions and EPCs. Mechanistic studies suggest that CCM3 suppresses Cav1/caveolae-mediated cellular trafficking and complex formation of the mTORC1 signaling proteins. Genetic deficiency of Raptor (mTORC1), but not of Rictor (mTORC2), prevents CCM lesion formation in the Pdcd10BECKO model. Importantly, mTORC1 pharmacological inhibitor Rapamycin ameliorate the CCM pathogenesis in the Pdcd10BECKO mice, by suppressing lesion-forming EPC expansion while enhancing BBB maturation. Our data suggest that CCM3 is critical for maintaining BBB integrity, and CCM3 loss-induced mTORC1 signaling in brain EPCs initiate the CCM pathogenesis.
2024-06-12 | GSE246598 | GEO
Project description:Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease caused by tuberous sclerosis complex 1/2 (TSC1/2) gene mutations resulting in activation of the mechanistic target of rapamycin complex 1 (mTORC1). A subset of LAM patients develops pulmonary vascular remodeling and pulmonary hypertension. To model LAM disease, we utilized an mTORC1 gain-of-function mouse model with a Tsc2 knock-out (Tsc2KO) specific to lung mesenchyme (Tbx4LME-CreTsc2fl/fl), similar to the mesenchyme specific genetic alterations seen in human disease. As early as 8 weeks of age, ECs from Tbx4LME-CreTsc2fl/fl mice exhibited marked transcriptomic changes despite absence of morphological changes to the distal lung microvasculature. In contrast, 1 year old Tbx4LME-CreTsc2fl/fl mice spontaneously developed pulmonary vascular remodeling with increased medial thickness. We subsequently performed single cell RNA-sequencing of 1 year old mouse lung and identified paracrine ligands originating from Tsc2KO mesenchyme impacting arterial endothelial cells. These cells contained transcriptionally altered genes including those in pathways associated with blood vessel remodeling, highlighting the pathogenic importance of the mesenchymal-endothelial cell axis.
2024-01-25 | GSE249634 | GEO
Project description:The PI3K-AKT-mTOR pathway is commonly dysregulated in cancer. Rapalogs exhibit modest clinical benefit likely due to their lack of effects on 4E-BP1. We hypothesized that bi-steric mTORC1-selective inhibitors would have greater potential for clinical benefit than rapalogs in tumors with mTORC1 dysfunction. We assessed this hypothesis in tumor models with high mTORC1 activity both in vitro and in vivo. Bi-steric inhibitors had strong growth inhibition, eliminated phosphorylated 4EBP1, and induced more apoptosis than rapamycin or MLN0128. Multi-omic analysis showed extensive effects of the bi-steric inhibitors in comparison to rapamycin. De novo purine synthesis was markedly and selectively inhibited by bi-sterics through reduction in JUN and its downstream target PRPS1 and appeared to be the cause of apoptosis. Hence, bi-steric mTORC1-selective inhibitors are a novel therapeutic strategy to treat tumors driven by mTORC1 hyperactivation.
2023-11-08 | GSE236742 | GEO