Selvaggio2020 - Microenvironment control of hybrid Epithelial-Mesenchymal phenotypes
Ontology highlight
ABSTRACT:
SUBMITTER: 
Claudine Chaouiya
PROVIDER: MODEL2004040001 | BioModels | 2020-06-30
REPOSITORIES: BioModels
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| MODEL2004040001?filename=Selvaggio_etal_2020.sbml | Other |
Items per page: 5 1 - 1 of 1 |
Similar Datasets
Project description:This model is an expansion of the Regan2022 - Mechanosensitive EMT model (MODEL2208050001); it includes a TGFβ signaling module and autocrine signaling in mesenchymal cells. The expanded 150-node (630 link) modular model undergoes EMT triggered by biomechanical and growth signaling crosstalk, or by TGFβ. As its predecessor, this model also reproduces the ability of the core EMT transcriptional network to maintain distinct epithelial, hybrid E/M and mesenchymal states, as well as EMT driven by mitogens such as EGF on stiff ECM. We also reproduce the observed lack of stepwise MET, in that our model's dynamics does not pass through the hybrid E/M state during MET. We show that in the absence of strong autocrine signals such as TGFβ (not included in this version), cells cannot maintain their mesenchymal state in the absence of mitogens, on softer matrices, or at high cell density. In contrast, potent autocrine signaling can stabilize the mesenchymal state in all but very dense monolayers on soft ECM. This expanded model also reproduces the inhibitory effects of TGFβ on proliferation and anoikis resistance in mesenchymal cells, as well as its ability to trigger apoptosis on soft ECM vs. EMT on stiff matrices. The model offers several experimentally testable predictions related to the effect of neighbors on partial vs. full EMT, the tug of war between mitosis and the maintenance of migratory hybrid E/M states, as well as cell cycle defects in dynamic, heterogeneous populations of epithelial, hybrid E/M and mesenchymal cells.
2023-12-13 | MODEL2208050002 | BioModels
Project description:This file contains a 136-node modular Boolean network model of EMT triggered by biomechanical and growth signaling crosstalk, linked to a published network of epithelial contact inhibition, proliferation, and apoptosis (MODEL2006170001). This model reproduces the ability of the core EMT transcriptional network to maintain distinct epithelial, hybrid E/M and mesenchymal states, as well as EMT driven by mitogens such as EGF on stiff ECM. We also reproduce the observed lack of stepwise MET, in that our model's dynamics does not pass through the hybrid E/M state during MET. We show that in the absence of strong autocrine signals such as TGFβ (not included in this version), cells cannot maintain their mesenchymal state in the absence of mitogens, on softer matrices, or at high cell density.
2023-12-13 | MODEL2208050001 | BioModels
Project description:FAT1, a protocadherin, is among the most frequently mutated genes in human cancers1-5. However, the role and the molecular mechanisms by which FAT1 mutations control tumour initiation and progression are poorly understood. In the present study we used different mouse cancer models including skin squamous cell carcinoma (SCC) and lung tumours we found that Fat1 deletion accelerated tumour 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 tumour stemness and spontaneous metastasis. Transcriptional and chromatin profiling revealed that Yap1 and Sox2 are involved in promoting and stabilizing hybrid EMT state. To unravel the molecular mechanisms by which FAT1 (a protein located on the plasma membrane), lead to the transcriptional changes, we performed phosphor-proteomic analysis of A388 FAT1 WT human SCC cell lines and A388 FAR1 CRISPR KO. This analysis 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 tumours with important implications for cancer therapy. Altogether, our studies revealed that Fat1 loss of function promotes tumour initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state.
2021-01-18 | PXD022268 | Pride
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 | 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 | 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 | 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:Metastasis consists of sequential steps initiated by cancer cells invading from the primary tumor site into neighboring tissues, followed by entry into the circulatory system and completed by extravasation and growth in distal organs. Circulating tumor cells, thus, encounter and adapt to multiple environmental changes during this transition. Epithelial-to-mesenchymal transition (EMT) is a developmental program that consists of loss of epithelial features concomitant with acquisition of mesenchymal features. Activation of EMT in cancer facilitates acquisition of aggressive traits and cancer invasion. EMT plasticity (EMP), the dynamic transition between multiple hybrid states in which cancer cells display both epithelial and mesenchymal phenotypes, confers survival advantages for cancer cells in the constantly changing environment. Therefore, understanding the molecular mechanisms regulating intermediate phenotypic states along the E–M spectrum is critical. Core EMT transcription factors (EMT-TFs), ZEB, SNAI and TWIST families, play an important role in EMT and its plasticity. In the present study we characterize FLASH as a regulator of EMP and multiple EMT-TFs. We demonstrate that loss of FLASH gives rise to a hybrid E/M phenotype with high epithelial scores even in the presence of TGFβ, as determined by computational methods using expression of predetermined sets of epithelial and mesenchymal genes. We demonstrate that FLASH is regulating expression of multiple cell junction proteins with an established role in cancer progression and that its role in EMT is independent of its histone biogenesis role. Further, we show that FLASH expression in cancer lines is inversely correlated with the epithelial score, consistent with its function as a repressor of the epithelial phenotype. Nonetheless, activation of a distinct set of mesenchymal markers concomitant with epithelial markers reveals the complex role of FLASH in EMT and indicates that intermediate E/M states could arise from opposing control by FLASH on different families of EMT-TFs.
2023-12-14 | GSE245621 | GEO
Project description:Epithelial-mesenchymal transition (EMT), a switch of polarized epithelial cells to a migratory, fibroblastoid phenotype, is considered a key process driving tumor cell invasiveness and metastasis. Using breast cancer cell lines as a model system, we sought to discover gene-expression signatures of EMT with clinical and mechanistic relevance. A supervised comparison of epithelial and mesenchymal breast cancer lines defined a 200-gene EMT signature that was prognostic across multiple breast cancer cohorts. Immunostaining of LYN, a top-ranked EMT signature gene and Src-family tyrosine kinase, was associated with significantly shorter overall survival (P=0.02), and correlated with the basal-like (“triple-negative”) phenotype. In mesenchymal breast cancer lines, RNAi-mediated knockdown of LYN inhibited cell migration and invasion, but not proliferation. Dasatinib, a dual-specificity tyrosine kinase inhibitor, also blocked invasion (but not proliferation) at nanomolar concentrations that inhibit LYN kinase activity, suggesting that LYN is a likely target and invasion a relevant endpoint for dasatinib therapy. Our findings define a prognostically-relevant EMT signature in breast cancer, and identify LYN as a mediator of invasion and possible new therapeutic target (and theranostic marker for dasatinib response), with particular relevance to clinically-aggressive basal-like breast cancer. Cell Line: cell line(epithelial-like/fibroblast-like/normal breast fibroblasts) Keywords: Logical Set Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. HEEBO oligonucleotide microarrays from the Stanford Functional Genomics Facility were used to perform gene expression profiling of 20 human breast cell lines, in comparison to a universal RNA reference. Expression data were analyzed by Significance Analysis of Microarrays to identify a 200-gene signature characteristic of EMT.
2010-04-11 | E-GEOD-13915 | biostudies-arrayexpress