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ABSTRACT:
PROVIDER: PRJEB29597 | ENA |
REPOSITORIES: ENA
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Project description:Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the Hippo pathway
| PRJNA503479 | ENA
Project description:Loss of FAT1 promotes resistance to CDK4/6 inhibitors. This study was to compare the differential mRNA expression of FAT1 crispr cells with parental cells, to identify the underlying mechanisms of resistance.
2018-11-02 | GSE122088 | GEO
Project description:Failure to achieve complete elimination of triple negative breast cancer (TNBC) stem cells after adjuvant therapy is associated with poor outcomes. Aldehyde dehydrogenase 1 (ALDH1) is a marker of breast cancer stem cells (BCSCs), and its enzymatic activity regulates tumor stemness. Identifying upstream targets to control ALDH+ cells may facilitate TNBC tumor suppression. Here, we show that KK-LC-1 determines the stemness of TNBC ALDH+ cells via binding with FAT1 and subsequently promoting its ubiquitination and degradation. This compromised the Hippo pathway and led to nuclear translocation of YAP1 and ALDH1A1 transcription. These findings identified the KK-LC-1-FAT1-Hippo-ALDH1A1 pathway in TNBC ALDH+ cells as a therapeutic target. To reverse the malignancy due to KK-LC-1 expression, we employed a novel computational approach and discovered Z839878730 (Z8) as an small-molecule inhibitor which may disrupt KK-LC-1 and FAT1 binding. We demonstrate that Z8 suppressed TNBC tumor growth via a mechanism that reactivated the Hippo pathway and decreased TNBC ALDH+ cell stemness and viability.
2023-04-12 | PXD040200 | Pride
Project description:Breast cancer has constantly been the leading causes of death in women, and hormone receptor (HR) positive, HER2 negative is the majority subtype. Treatment modalities for HR (+) metastatic breast cancer (mBC) includes endocrine therapy (tamoxifen, fulvestrant, aromatase inhibitors) in addition to targeted therapies (CDK4/6 inhibitors, PI3K/AKT/mTOR inhibitors, histone deacetylase (HDAC) inhibitors, and others. The hippo pathway LATS1/2-YAP/TAZ-TEAD signaling cascade is a fundamentally important pathway that governs multiple essential biological functions in cell biology and cancer biology. YAP/TAZ are often viewed as pro-tumorogenic, however, recent studies support a role of YAP as a tumor suppressor in HR (+) breast cancer due to its inhibition of estrogen signaling. Few studies have investigated the link between HDAC inhibitors and the Hippo pathway. In our study, we demonstrate that HDAC inhibitors induce transcriptional downregulation of YAP expression, while conversely activating a TEAD mediated transcriptional program with upregulation of many Hippo pathway canonical genes. We further identified 4 genes (CCDC80, GADD45A, F3, TGFB2) that were upregulated by HDAC inhibitors and associated with significantly improved survival in a HR (+) breast cancer cohort. We also correlate in patients samples from a clinical cohort of HR (+) metastatic breast cancer that upregulation of Hippo downstream genes are correlated with improved outcomes. Our study provide a novel mechanistic explanation for the clinical benefit of HDAC inhibitors, while providing further experimental support that Hippo-TEAD transcriptional activation profile is associated with better outcomes in HR (+) breast cancer.
2025-03-05 | GSE263971 | GEO
Project description:FAT1, a protocadherin, is among the most frequently mutated genes in human cancers. However, the role and the molecular mechanisms by which FAT1 mutations control tumor initiation and progression are poorly understood. Here, using different mouse cancer models including skin squamous cell carcinoma (SCC) and lung tumors we found that Fat1 deletion accelerated tumor initiation and malignant progression and promoted hybrid epithelial to mesenchymal transition (EMT) phenotype. This hybrid EMT state was also found in FAT1 mutated human SCCs. Fat1 deleted skin SCCs presented increased tumor stemness and spontaneous metastasis. Transcriptional and chromatin profiling combined with proteomic analyses and mechanistic studies revealed that FAT1 loss of function activates a CAMK2/CD44/SRC axis that promotes YAP/ZEB1 nuclear translocation and stimulates the mesenchymal state, as well as a CAMK2-EZH2 axis that promotes activation of SOX2, which sustains the epithelial state. This comprehensive analysis also identified drug resistance and vulnerabilities in FAT1 deficient tumors with important implications for cancer therapy. Altogether, our studies revealed that Fat1 loss of function promotes tumor initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state.
2020-12-04 | GSE158505 | GEO
Project description:FAT1, a protocadherin, is among the most frequently mutated genes in human cancers. However, the role and the molecular mechanisms by which FAT1 mutations control tumor initiation and progression are poorly understood. Here, using different mouse cancer models including skin squamous cell carcinoma (SCC) and lung tumors we found that Fat1 deletion accelerated tumor initiation and malignant progression and promoted hybrid epithelial to mesenchymal transition (EMT) phenotype. This hybrid EMT state was also found in FAT1 mutated human SCCs. Fat1 deleted skin SCCs presented increased tumor stemness and spontaneous metastasis. Transcriptional and chromatin profiling combined with proteomic analyses and mechanistic studies revealed that FAT1 loss of function activates a CAMK2/CD44/SRC axis that promotes YAP/ZEB1 nuclear translocation and stimulates the mesenchymal state, as well as a CAMK2-EZH2 axis that promotes activation of SOX2, which sustains the epithelial state. This comprehensive analysis also identified drug resistance and vulnerabilities in FAT1 deficient tumors with important implications for cancer therapy. Altogether, our studies revealed that Fat1 loss of function promotes tumor initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state.
2020-12-04 | GSE158503 | GEO
Project description:FAT1, a protocadherin, is among the most frequently mutated genes in human cancers. However, the role and the molecular mechanisms by which FAT1 mutations control tumor initiation and progression are poorly understood. Here, using different mouse cancer models including skin squamous cell carcinoma (SCC) and lung tumors we found that Fat1 deletion accelerated tumor initiation and malignant progression and promoted hybrid epithelial to mesenchymal transition (EMT) phenotype. This hybrid EMT state was also found in FAT1 mutated human SCCs. Fat1 deleted skin SCCs presented increased tumor stemness and spontaneous metastasis. Transcriptional and chromatin profiling combined with proteomic analyses and mechanistic studies revealed that FAT1 loss of function activates a CAMK2/CD44/SRC axis that promotes YAP/ZEB1 nuclear translocation and stimulates the mesenchymal state, as well as a CAMK2-EZH2 axis that promotes activation of SOX2, which sustains the epithelial state. This comprehensive analysis also identified drug resistance and vulnerabilities in FAT1 deficient tumors with important implications for cancer therapy. Altogether, our studies revealed that Fat1 loss of function promotes tumor initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state.
2020-12-04 | GSE158502 | GEO
Project description:FAT1, a protocadherin, is among the most frequently mutated genes in human cancers. However, the role and the molecular mechanisms by which FAT1 mutations control tumor initiation and progression are poorly understood. Here, using different mouse cancer models including skin squamous cell carcinoma (SCC) and lung tumors we found that Fat1 deletion accelerated tumor initiation and malignant progression and promoted hybrid epithelial to mesenchymal transition (EMT) phenotype. This hybrid EMT state was also found in FAT1 mutated human SCCs. Fat1 deleted skin SCCs presented increased tumor stemness and spontaneous metastasis. Transcriptional and chromatin profiling combined with proteomic analyses and mechanistic studies revealed that FAT1 loss of function activates a CAMK2/CD44/SRC axis that promotes YAP/ZEB1 nuclear translocation and stimulates the mesenchymal state, as well as a CAMK2-EZH2 axis that promotes activation of SOX2, which sustains the epithelial state. This comprehensive analysis also identified drug resistance and vulnerabilities in FAT1 deficient tumors with important implications for cancer therapy. Altogether, our studies revealed that Fat1 loss of function promotes tumor initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state.
2020-12-04 | GSE158501 | GEO
Project description:FAT1, a protocadherin, is among the most frequently mutated genes in human cancers. However, the role and the molecular mechanisms by which FAT1 mutations control tumor initiation and progression are poorly understood. Here, using different mouse cancer models including skin squamous cell carcinoma (SCC) and lung tumors we found that Fat1 deletion accelerated tumor initiation and malignant progression and promoted hybrid epithelial to mesenchymal transition (EMT) phenotype. This hybrid EMT state was also found in FAT1 mutated human SCCs. Fat1 deleted skin SCCs presented increased tumor stemness and spontaneous metastasis. Transcriptional and chromatin profiling combined with proteomic analyses and mechanistic studies revealed that FAT1 loss of function activates a CAMK2/CD44/SRC axis that promotes YAP/ZEB1 nuclear translocation and stimulates the mesenchymal state, as well as a CAMK2-EZH2 axis that promotes activation of SOX2, which sustains the epithelial state. This comprehensive analysis also identified drug resistance and vulnerabilities in FAT1 deficient tumors with important implications for cancer therapy. Altogether, our studies revealed that Fat1 loss of function promotes tumor initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state.
2020-12-04 | GSE158500 | GEO
Project description:Inactivating mutations in SMARCA4 (BRG1), a key SWI/SNF chromatin remodelling gene, underlie small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). To reveal its druggable vulnerabilities, we perform kinase-focused RNAi screens and uncover that SMARCA4-deficient SCCOHT cells are highly sensitive to the inhibition of cyclin-dependent kinase 4/6 (CDK4/6). SMARCA4 loss causes profound downregulation of cyclin D1, which limits CDK4/6 kinase activity in SCCOHT cells and leads to in vitro and in vivo susceptibility to CDK4/6 inhibitors. SCCOHT patient tumors are deficient in cyclin D1 yet retain the retinoblastoma-proficient/p16INK4a-deficient profile associated with positive responses to CDK4/6 inhibitors. Thus, our findings indicate that CDK4/6 inhibitors, approved for a breast cancer subtype addicted to CDK4/6 activation, could be repurposed to treat SCCOHT. Moreover, our study suggests a novel paradigm whereby critically low oncogene levels, caused by loss of a driver tumor suppressor, may also be exploited therapeutically.
2019-02-04 | GSE120298 | GEO