A SIX1/EYA2 small molecule inhibitor disrupts EMT and metastasis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA635948 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11879377_1.fastq.gz | Fastqsanger.gz | |||
| SRR11879377_2.fastq.gz | Fastqsanger.gz | |||
| SRR11879378_1.fastq.gz | Fastqsanger.gz | |||
| SRR11879378_2.fastq.gz | Fastqsanger.gz | |||
| SRR11879379_1.fastq.gz | Fastqsanger.gz |
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Project description:This study identified a novel compound reverses SIX1-mediated EMT and metastasis in breast cancer
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Project description:Metastasis is the major cause of mortality for patients with cancer, and dysregulation of developmental signaling pathways can significantly contribute to the metastatic process. The Sine oculis homeobox homolog 1 (SIX1)/eyes absent (EYA) transcriptional complex plays a critical role in the development of multiple organs and is typically downregulated after development is complete. In breast cancer, aberrant expression of SIX1 has been demonstrated to stimulate metastasis through activation of TGFβ signaling and subsequent induction of epithelial-mesenchymal transition (EMT). In addition, SIX1 can induce metastasis via non-cell autonomous means, including activation of GLI-signaling in neighboring tumor cells and activation of VEGFC-induced lymphangiogenesis. Thus, targeting SIX1 would be expected to inhibit metastasis while conferring limited side effects. However, transcription factors are notoriously difficult to target, and thus novel approaches to inhibit their action must be taken. Here we identified a novel small molecule compound, NCGC00378430 (abbreviated as 8430), that reduces the SIX1/EYA2 interaction. 8430 partially reversed transcriptional and metabolic profiles mediated by SIX1 overexpression and reversed SIX1-induced TGFβ signaling and EMT. 8430 was well tolerated when delivered to mice and significantly suppressed breast cancer-associated metastasis in vivo without significantly altering primary tumor growth. Thus, we have demonstrated for the first time that pharmacologic inhibition of the SIX1/EYA2 complex and associated phenotypes is sufficient to suppress breast cancer metastasis. SIGNIFICANCE: These findings identify and characterize a novel inhibitor of the SIX1/EYA2 complex that reverses EMT phenotypes suppressing breast cancer metastasis.
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Project description:Transcriptome analysis of EYA2 non-expressing pancreatic cancer cell lines with stable transfectant overexpressing EYA2
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Project description:Inappropriate activation of developmental pathways is a well-recognized tumor-promoting mechanism. Here we show that overexpression of the homeoprotein Six1, normally a developmentally restricted transcriptional regulator, increases Transforming Growth Factor-beta (TGF-beta) signaling in mammary carcinoma cells and induces an epithelial to mesenchymal transition (EMT) that is in part dependent on its ability to increase TGF-beta signaling. TGF-beta signaling and EMT have been implicated in metastatic dissemination of carcinoma. Using spontaneous and experimental metastasis mouse models, we demonstrate that Six1 overexpression promotes breast cancer metastasis. In addition, we show that, like its induction of EMT, Six1-induced experimental metastasis is dependent on its ability to activate TGF-beta signaling. Importantly, in human breast cancers Six1 significantly correlates with nuclear Smad3, and thus increased TGF-beta signaling. Further, breast cancer patients whose tumors overexpress Six1 have a shortened time to relapse and metastasis, and an overall decrease in survival. Finally, we show that the effects of Six1 on tumor progression likely extend beyond breast cancer, since its overexpression correlates with adverse outcomes in numerous other cancers, including brain, cervical, prostate, colon, kidney, and liver, amongst others. Our findings argue that Six1, acting through TGF-beta signaling and EMT, is a powerful and global promoter of cancer metastasis.
2010-08-21 | GSE23655 | GEO
Project description:The homeodomain transcription factor SIX1 plays a critical role in embryogenesis, is not expressed in normal adult tissue, but is expressed in many malignancies, including cervical cancer. SIX1 drives the progression of HPV16-immortalized human keratinocytes (HKc/HPV16) toward malignancy: HKc/HPV16 express high levels of SIX1 mRNA and protein; overexpression of SIX1 in HKc/HPV16 produces pre-malignant, differentiation-resistant lines (HKc/DR); SIX1 overexpression in HKc/DR induces tumorigenicity. In this paper, we explore the consequences of inhibition of SIX1 expression in premalignant HKc/DR. Only partial inhibition of SIX1 expression could be obtained in HKc/DR by RNA interference. Decreased SIX1 expression (up to 80%) in HKc/DR resulted in slower proliferation, decreased HPV16-E6/E7 mRNA levels, and increased p53 protein levels. Gene expression changes induced in HKc/DR by anti-SIX1 shRNA were indicative of mesenchymal-epithelial transition (EMT) and changes in TGF-beta signaling. We conclude that HPV16-transformed cells depend on SIX1 for survival, continuous HPV16 E6/E7 gene expression and EMT.
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Project description:Transcriptome analysis of EYA2 non-expressing pancreatic cancer cell lines with stable transfectant overexpressing EYA2 We analyzed Panc2.5 and Panc3.014 stable transfectant (overexpressing EYA2) and control (empty pcDNA6.2/cLumio-DEST vector) cell transcriptomes using the Affymetrix Exon Array ST1.0 platform. Statistical analysis of gene expression array data was completed with Partek Genomic Suite 6.4 software.
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Project description:Glioblastoma ranks among the most lethal of primary brain malignancies, with glioblastoma stem cells (GSCs) at the apex of tumor cellular hierarchies. Here, to discover novel therapeutic GSC targets, we interrogated gene expression profiles from GSCs, differentiated glioblastoma cells (DGCs), and neural stem cells (NSCs), revealing EYA2 as preferentially expressed by GSCs. Targeting EYA2 impaired GSC maintenance and induced cell cycle arrest, apoptosis, and loss of self-renewal. EYA2 displayed novel localization to centrosomes in GSCs, and EYA2 tyrosine (Tyr) phosphatase activity was essential for proper mitotic spindle assembly and survival of GSCs. Inhibition of the EYA2 Tyr phosphatase activity, via genetic or pharmacological means, mimicked EYA2 loss in GSCs in vitro and extended the survival of tumor-bearing mice. Supporting the clinical relevance of these findings, EYA2 portends poor patient prognosis in glioblastoma. Collectively, our data indicate that EYA2 phosphatase function plays selective critical roles in the growth and survival of GSCs, potentially offering a high therapeutic index for EYA2 inhibitors.
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Project description:Carcinoma cells can acquire key malignant traits by reprogramming their differentiation state via an epithelial-to-mesenchymal transition (EMT). Cancer cells that undergo EMT become invasive and resist a wide range of therapies including most chemotherapy drugs and radiation. Such cells are also able to efficiently seed primary and metastatic tumors, making them functionally indistinguishable from tumor-initiating or cancer stem-like cells (TICs or CSCs). Therefore, there is significant interest in finding vulnerabilities of cancer cells that have undergone EMT. A potent EMT-selective small molecule was discovered through a large-scale chemical screen. We used microarray analysis to understand the biological effects of this compound. HMLE_ctrl (human MECs, infected with a pBabe-shGFP retrovirus) and HMLE_Twist (human MECs, infected with a pBabe-Twist retrovirus) cells were treated with solvent control (DMSO), 5 µM or 10 µM of Cmp302 for 6 hours. Microarray analysis was performed to profile global gene expression.
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Project description:Carcinoma cells can acquire key malignant traits by reprogramming their differentiation state via an epithelial-to-mesenchymal transition (EMT). Cancer cells that undergo EMT become invasive and resist a wide range of therapies including most chemotherapy drugs and radiation. Such cells are also able to efficiently seed primary and metastatic tumors, making them functionally indistinguishable from tumor-initiating or cancer stem-like cells (TICs or CSCs). Therefore, there is significant interest in finding vulnerabilities of cancer cells that have undergone EMT. A potent EMT-selective small molecule was discovered through a large-scale chemical screen. We used microarray analysis to understand the biological effects of this compound.
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