AXL is a putative tumor suppressor and dormancy regulator in prostate cancer
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ABSTRACT:
PROVIDER: PRJNA487645 | ENA |
REPOSITORIES: ENA
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Project description:To understand how AXL overexpression induces aggregation of prostate cancer cells, microarray analysis from prostate cancer cell lines was used to observe differences in gene expression of cells with high versus low aggregation potential upon AXL overexpression.
2018-10-09 | GSE119003 | GEO
Project description:Prostate cancer bone metastasis remains lethal and incurable, and often arises years after elimination of the primary tumor. It is unclear what underlies the decades-long clinical latency before recurrence, but evidence points to the existence of dormant residual tumor cells that disseminated before the primary tumor was eliminated. To design therapies to prevent progression of disseminated tumor cells (DTC) into lethal metastases, it is crucial to understand the mechanism(s) underlying this dormancy. The current study functionally validated our previous observation that implicated the GAS6/AXL axis in mediating DTC dormancy in the bone marrow. AXL-null and AXL-overexpressing prostate cancer cell lines were generated to determine if AXL was necessary and/or sufficient for dormancy. Characterization of these cells in vitro and using in vivo mouse models of DTC growth demonstrated that AXL was indeed sufficient to induce dormancy, but was unable to maintain it long-term and was not absolutely required for a dormancy period. Clinically, AXL expression correlated with longer survival in prostate cancer patients, and AXL was not expressed by cancer cells in primary or metastatic tissue. These data point to a tumor-suppressive role for AXL in prostate cancer, and future work is required to determine if AXL is expressed on human bone marrow DTCs. IMPLICATIONS: The ability of AXL to initiate but not maintain dormancy, coupled with its dispensability, suggests that targeting AXL alone will not prevent lethal metastatic outgrowth, and likely a cooperative network of factors exists to mediate long-term cellular dormancy.
| S-EPMC6359976 | biostudies-literature
Project description:EHF is an essential regulator of mammary alveolar lineage differentiation and putative suppressor of breast tumorigenesis
| PRJNA1083897 | ENA
Project description:We report the comparative investigation of gene expression profiles between genetic inactivation AXL cell and AXL wild type cells in two independent We found a list of AXL signaling target genes that are important for tumor invasion and angiogenesis.
2020-04-03 | GSE125994 | GEO
Project description:The tumor suppressor BRCA1 is a translational regulator
| PRJNA490557 | ENA
Project description:This SuperSeries is composed of the following subset Series: GSE35311: Integrative array-based approach identifies MZB1 as a frequently methylated putative tumor-suppressor in hepatocellular carcinoma (expression) GSE35312: Integrative array-based approach identifies MZB1 as a frequently methylated putative tumor-suppressor in hepatocellular carcinoma (MeDIP) Refer to individual Series
2012-03-30 | E-GEOD-35313 | 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 | GSE102368 | GEO
Project description:Seed maturation, dormancy and germination are distinct physiological processes. Transition from maturation to dormancy, and from dormancy into germination are not only critical developmental phases in the plant life cycle but are also important agricultural traits. These developmental processes and their phase transitions are fine determined and coordinately regulated by genetic makeup and environmental cues. SCARECROW-LIKE15 (SCL15) has been demonstrated to be essential for repressing the seed maturation programme in vegetative tissues (Gao et al., Nat Commun, 2015, 6:7243). Here we report that SCL15 is also important for seed dormancy maintenance, germination timing and seed vigor performance based on the effects of SCL15 mutation on plant germination, growth and reproduction when compared with wild type Arabidopsis and over-expression lines 35S:SCL15 and Napin:SCL15. Seed dormancy is enhanced by the mutation of SCL15 in a GA signaling dependent way, indicating that SCL15 plays a negative role for primary dormancy release. Seed germination is positively regulated by SCL15 through interaction with ABA, GA and auxin signaling. SCL15 acts as positive regulator of seed vigor and effect of SCL15 mRNA abundance on seed reserve accumulation and seed development during late embryogenesis may contribute to the seed vigor performance.
2020-11-04 | GSE160707 | GEO
Project description:Disseminated cancer cells (DCCs) that escape the primary site can seed in distal tissues, but may take several years, or even decades to grow out into overt metastases, a phenomenon termed tumor dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully model or characterize dormancy within melanoma. Here, we show that age-related changes in the lung microenvironment facilitate a permissive niche for efficient outgrowth of disseminated dormant tumor cells, in contrast to the aged skin, where age-related changes suppress melanoma growth but drive dissemination. A model of melanoma progression that addresses these microenvironmental complexities is the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state1-3. We have previously shown that dermal fibroblasts are key orchestrators of promoting phenotype switching in primary melanoma tumors via changes in the secretion of soluble factors during aging4-8. Our new data identifies Wnt5A as a master regulator of activating melanoma DCC dormancy within the lung, which initially enables efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of the soluble Wnt antagonist sFRP1, which inhibits Wnt5A, enabling efficient metastatic outgrowth. Further, we have identified the tyrosine kinase receptors AXL and MER as promoting a dormancy-toreactivation axis respectively. Overall, we find that age-induced changes in distal metastatic microenvironments promotes efficient reactivation of dormant melanoma cells in the lung.
2022-03-03 | MSV000088977 | MassIVE
Project description:Elevated expression and activity of the epidermal growth factor receptor (EGFR) is associated with development and progression of head and neck cancer (HNC) and a poor prognosis. Clinical trials with EGFR tyrosine kinase inhibitors (TKIs; eg. erlotinib) have been disappointing in HNC. To investigate the mechanisms mediating resistance to these agents, we developed a HNC cell line (HN5-ER) with acquired erlotinib resistance. In contrast to parental HN5 HNC cells, HN5-ER cells exhibited an epithelial-mesenchymal (EMT) phenotype with increased migratory potential, reduced E-cadherin and epithelial-associated miRNAs, and elevated vimentin expression. Phosphorylated RTK profiling identified Axl activation in HN5-ER cells. Growth and migration of HN5-ER cells was blocked with a specific Axl inhibitor, R428, and R428 re-sensitized HN5-ER cells to erlotinib. Microarray analysis of HN5-ER cells confirmed the EMT phenotype associated with acquired erlotinib resistance, and identified activation of gene expression associated with cell migration and inflammation pathways. Moreover, increased expression and secretion of interleukin (IL)-6 and IL-8 in HN5-ER cells suggested a role for inflammatory cytokine signaling in EMT and erlotinib resistance. Expression of the tumor suppressor miR-34a was reduced in HN5-ER cells and increasing its expression abrogated Axl expression and reversed erlotinib resistance. Finally, analysis of 302 HNC patients revealed that high tumor Axl mRNA expression was associated with poorer survival (HR 1.66, p=0.007). In summary, our results identify Axl as a key mediator of acquired erlotinib resistance in HNC and suggest that therapeutic inhibition of Axl by small molecule drugs or specific miRNAs might overcome anti-EGFR therapy resistance. Differential gene expression between parental and acquired erlotinib resistant head and neck cancer cell lines of HN5.
2013-08-10 | E-GEOD-49135 | biostudies-arrayexpress