AXL-TBK1 driven AKT3 activation promotes metastasis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1148385 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30248859.fastq.gz | Fastqsanger.gz | |||
| SRR30248860.fastq.gz | Fastqsanger.gz | |||
| SRR30248861.fastq.gz | Fastqsanger.gz | |||
| SRR30248862.fastq.gz | Fastqsanger.gz | |||
| SRR30248863.fastq.gz | Fastqsanger.gz |
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Project description:The receptor tyrosine kinase AXL promotes tumor progression, metastasis and therapy resistance through the induction of epithelial-mesenchymal transition (EMT). Here, we report that activation of AXL results in TANK-binding kinase 1 (TBK1) phosphorylation, subsequent TBK1-dependent phosphorylation of AKT3 (pAKT3) and nuclear accumulation of pAKT3 and the EMT transcription factor (EMT-TF) Snail. Mechanistically, we show that (i) TBK1 directly binds and phosphorylates AKT3, in an mTORC1 dependent manner. Once activated, AKT3 interacts with Snail and promotes the accumulation of nuclear Snail to drive EMT. Congruently, in human pancreatic ductaladenocarcinoma tissue, nuclear AKT3 co-localizes with Snail and correlates with worse clinical outcome. AKT3 knockout in tumor cells significantly reduced metastatic spread in mice suggesting that selective AKT3 inhibition represents a novel therapeutic avenue for targeting EMT in aggressive cancers.
2024-12-17 | GSE274874 | GEO
Project description:We evaluated soluble AXL (sAXL or batiraxcept), a decoy receptor that can potently inhibit AXL signaling, as a single agent or in combination with docetaxel or carboplatin to treat prostate cancer (PCa) bone metastases. We used intratibial injection of multiple patient-derived xenografts with different characteristics, reflecting a traditional phase II clinical trial without pre-selection for a particular tumor characteristic. Inhibition of tyrosine kinase receptor AXL was highly effective as a single agent and showed additive effects when combined with docetaxel or carboplatin in suppressing PCa tumor growth in the bone and in suppressing metastasis to the lung. AXL inhibition suppressed critical cancer stem cell gene expression and significantly decreased proliferation and metastasis through suppression of E2F1 and NuSAP1. Our findings provide compelling preclinical data for testing batiraxcept in patients with prostate cancer with bone metastases.
2025-01-23 | GSE281461 | GEO
Project description:AXL is activated by its ligand GAS6 and is expressed in triple-negative breast cancer cells. We report that AXL is also detected in HER2+ breast cancer specimens where its expression correlates with poor patients’ survival. Using murine models of HER2+ breast cancer, AXL, but not Gas6, was found essential for metastasis. We determined that AXL is required for intravasation, extravasation and growth at the metastatic site. AXL is expressed in HER2+ cancers displaying EMT signatures and contributes to sustain EMT in murine tumors. Interfering with AXL in patient-derived xenograft impaired TGF-β-induced cell invasion. Lastly, pharmacological inhibition of AXL decreased the metastatic burden of mice developing HER2+ breast cancer. Our data identify AXL as a potential co-therapeutic target during the treatment of HER2+ breast cancers to limit metastasis.
2018-05-01 | GSE102368 | GEO
Project description:Akt is a robust oncogene that plays key roles in the development and progression of many cancers, including glioma. We evaluated the differential propensities of the Akt isoforms toward progression in the well-characterized RCAs/Ntv-a mouse model of PDGFB-driven low grade glioma. A constitutively active myristoylated form of Akt1 did not induce high-grade glioma (HGG). In stark contrast, Akt2 and Akt3 showed strong progression potential with 78% and 97% of tumors diagnosed as HGG, respectively. We further revealed that significant variations in polarity and hydropathy values among the Akt isoforms in both the pleckstrin homology domain (P domain) and regulatory domain (R domain) were critical in mediating glioma progression. Gene expression profiles from representative Akt-derived tumors indicated dominant and distinct roles for Akt3, consisting primarily of DNA repair pathways. TCGA data from human GBM closely reflected the DNA repair function, as Akt3 was significantly correlated with a 76 gene signature DNA repair panel. Consistently, compared to Akt1 and Akt2 overexpression models, Akt3-expressing human GBM cells had enhanced activation of DNA repair proteins, leading to increased DNA repair and subsequent resistance to radiation and temozolomide. Given the wide range of Akt3-amplified cancers, Akt3 may represent a key resistance factor. 5 different experimental conditions were compared (including GFP, PDGFB, PDGFB in conjunciton with Akt1, Akt2, or Akt3) with 3 mice per treatment
2015-02-24 | E-GEOD-66177 | biostudies-arrayexpress
Project description:AXL is activated by its ligand GAS6 and is expressed in triple-negative breast cancer cells. We report that AXL is also detected in HER2+ breast cancer specimens where its expression correlates with poor patients’ survival. Using murine models of HER2+ breast cancer, AXL, but not Gas6, was found essential for metastasis. We determined that AXL is required for intravasation, extravasation and growth at the metastatic site. AXL is expressed in HER2+ cancers displaying EMT signatures and contributes to sustain EMT in murine tumors. Interfering with AXL in patient-derived xenograft impaired TGF-β-induced cell invasion. Lastly, pharmacological inhibition of AXL decreased the metastatic burden of mice developing HER2+ breast cancer. Our data identify AXL as a potential co-therapeutic target during the treatment of HER2+ breast cancers to limit metastasis.
2018-05-01 | GSE102369 | GEO
Project description:Akt is a robust oncogene that plays key roles in the development and progression of many cancers, including glioma. We evaluated the differential propensities of the Akt isoforms toward progression in the well-characterized RCAs/Ntv-a mouse model of PDGFB-driven low grade glioma. A constitutively active myristoylated form of Akt1 did not induce high-grade glioma (HGG). In stark contrast, Akt2 and Akt3 showed strong progression potential with 78% and 97% of tumors diagnosed as HGG, respectively. We further revealed that significant variations in polarity and hydropathy values among the Akt isoforms in both the pleckstrin homology domain (P domain) and regulatory domain (R domain) were critical in mediating glioma progression. Gene expression profiles from representative Akt-derived tumors indicated dominant and distinct roles for Akt3, consisting primarily of DNA repair pathways. TCGA data from human GBM closely reflected the DNA repair function, as Akt3 was significantly correlated with a 76 gene signature DNA repair panel. Consistently, compared to Akt1 and Akt2 overexpression models, Akt3-expressing human GBM cells had enhanced activation of DNA repair proteins, leading to increased DNA repair and subsequent resistance to radiation and temozolomide. Given the wide range of Akt3-amplified cancers, Akt3 may represent a key resistance factor.
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Project description:The receptor tyrosine kinase AXL is associated with epithelial plasticity in several solid tumors including breast cancer and AXL-targeting agents are currently in clinical trials. We hypothesized that AXL is a driver of stemness traits in cancer by co-option of a regulatory function normally reserved for stem cells. AXL-expressing cells in human mammary epithelial ducts co-expressed markers associated with multipotency, and AXL inhibition abolished colony-formation and self-maintenance activities while promoting terminal differentiation in vitro. Axl-null mice did not exhibit a strong developmental phenotype, but enrichment of Axl+ cells was required for mouse mammary gland reconstitution upon transplantation, and Axl-null mice had reduced incidence of Wnt1-driven mammary tumors. An AXL-dependent gene signature is a feature of transcriptomes in basal breast cancers, and reduced patient survival irrespective of subtype. Our interpretation is that AXL regulates access to epithelial plasticity programs in MaSCs and, when coopted, maintains acquired stemness in breast cancer cells.
2020-08-25 | GSE156662 | GEO
Project description:Tumor metastasis is the major cause of death for prostate cancer (PCa) patients. However, the treatment options for metastatic PCa are very limited. Epithelial-mesenchymal transition (EMT) has been reported to be an indispensable step for tumor metastasis and is suggested to associate with acquisition of cancer stem cell (CSC) attributes. Herein we establish a EMT reporter system based on firefly or renilla luciferase reporter driven by promoters of CDH1 and VIM genes. High-throughput drug screening from an approved drug library identifies Amlexanox, a commonly used drug to treat aphthous ulcers, to be a strong EMT inhibitor. Amlexanox significantly suppresses PCa cell migration, metastasis and tumor initiation capacity. Mechanistically, the inhibitory effect of Amlexanox on EMT and cell mobility is acted through targeting the IKK-ɛ/ TBK1/ NF-κB signaling pathway. Considering the known safety as well as the pharmacokinetic and pharmacodynamic profile of Amlexanox, our findings suggest a great potential of repositioning Amlexanox as a new anti-metastatic drug for PCa.
2018-07-20 | GSE110206 | GEO
Project description:Aberrant expression of receptor tyrosine kinase AXL is linked to metastasis. AXL can be activated by its ligand GAS6 or by other kinases, but the signaling pathways conferring its metastatic activity are unknown. Here, we define the AXL-regulated phosphoproteome in breast cancer cells. We reveal that AXL stimulates the phosphorylation of a network of focal adhesion (FA) proteins culminating in faster FA disassembly. Mechanistically, AXL phosphorylate NEDD9 leading to its binding to CRKII which in turn associates with and orchestrates the phosphorylation of the pseudo-kinase PEAK1. We find that PEAK1 is in complex with the tyrosine kinase CSK to mediate the phosphorylation of PAXILLIN. Uncoupling of PEAK1 from AXL signaling decreases metastasis in vivo, but not tumor growth. Our results uncover a contribution of AXL signaling to FA dynamics, reveal a long sought-after mechanism underlying AXL metastatic activity, and identify PEAK1 as a therapeutic target in AXL positive tumors.
2020-04-15 | MSV000085293 | MassIVE
Project description:AXL is a receptor tyrosine kinase (RTK) which, together with TYRO3 and MER, belongs to the TAM receptor family. A ligand for AXL is growth arrest specific 6 (GAS6), which is able to bind all three TAMs with the highest affinity for AXL. AXL is overexpressed in a variety of different cancers, which correlates with poor prognosis, metastasis and drug resistance. However, its biology is still not fully understood and data concerning proteins that interact with this receptor are almost completely lacking. To identify mechanisms underlying the role of GAS6-AXL signaling in cancer, we established an AXL interactome using proximity-dependent biotin identification (BioID) assay. Experiments were conducted in HEK293 cells and human glioblastoma LN229 cells, which do not express and express AXL, respectively. The Gene Ontology (GO) analysis of biological processes indicated enrichment of proteins implicated in cell junction organization, axonogenesis, supramolecular fiber organization, angiogenesis and actin-related processes in bot, non-stimulated and GAS6-stimulated samples. Importantly, in samples with activated AXL, proteins implicated in actin-related processes were overrepresented. Consistent with this, we found that GAS6 stimulation triggered actin remodeling manifested by intense membrane ruffling and macropinocytosis. Our study provides comprehensive data about proteins interacting with AXL. Thus, the obtained results will help to understand the biology of the AXL receptor, particularly with respect to its involvement in cancer invasion.
2021-06-28 | PXD017933 | Pride