Upregulated Vav2 signaling promotes regenerative proliferation in squamous cell carcinoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE124019 | GEO | 2020/08/13
REPOSITORIES: GEO
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Project description:Signals emanating from Rho GTPases play pivotal roles in epidermal stem cell homeostasis. However, the agents regulating Rho GTPase output within the epidermal stem cell niche are poorly known. Here, we report that the Rho exchange factor Vav2 regulates the epidermal stem cell transcriptome in an age-dependent manner.
2023-10-24 | GSE140152 | GEO
Project description:Upregulated Vav2 signaling promotes regenerative proliferation in squamous cell carcinoma
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Project description:The small G-protein Rac1, a member of the Rho family of GTPases, is a central player in cancer progression and metastatic dissemination. Rac1 has been established as a bona fide effector of receptor tyrosine kinases, acting as a signaling node for growth factor-mediated responses such as motility, invasiveness, mitogenesis and gene expression. Previous studies demonstrated that Rac1 is aberrantly hyperactivated in aggressive cellular models of prostate cancer. Here we show that CRISPR-mediated knockout of Rac1 in prostate cancer cells leads to impaired proliferation and migration. Rac1-null cells display major alterations in gene expression, most notably affecting transcriptional programs associated with cell adhesion and extracellular matrix (ECM) regulation, but not those related to epithelial-to-mesenchymal (EMT) transition. Expression analysis of GEFs, the guanine nucleotide exchange factors responsible for Rac1 activation, followed by an unbiased RNAi screening, identified VAV2 as the foremost mediator of epidermal growth factor (EGF)-induced GTP loading onto Rac1 in prostate cancer cells. VAV2-deficient prostate cancer cells display significant proliferative and migratory defects, without noticeable changes in the expression of Rac1-regulated genes such as CDH1 and CDH3, indicating that VAV2 controls a discrete subset of Rac1-dependent responses. Finally, immunohistochemical assessment of VAV2 expression in human prostate specimens revealed significant VAV2 up-regulation in tumoral vs. non-tumoral areas. Our studies revealed important contributions of VAV2 to Rac1 activation in prostate cancer cells and highlight its potential prognostic value as a marker of prostate cancer progression.
2025-04-01 | GSE292590 | GEO
Project description:The guanosine triphosphatases of the Rho and Rac subfamilies regulate protumorigenic pathways and are activated by guanine nucleotide exchange factors (Rho GEFs), which could be potential targets for anticancer therapies. We report that two Rho GEFs, Vav2 and Vav3, play synergistic roles in breast cancer by sustaining tumor growth, neoangiogenesis, and many of the steps involved in lung-specific metastasis. The involvement of Vav proteins in these processes did not correlate with Rac1 and RhoA activity or cell migration, implying the presence of additional biological programs. Microarray analyses revealed that Vav2 and Vav3 controlled a vast transcriptional program in breast cancer cells through mechanisms that were shared between the two proteins, isoform-specific or synergistic. Furthermore, the abundance of Vav regulated transcripts was modulated by Rac1-dependent and Rac1-independent pathways. This transcriptome encoded therapeutically targetable proteins that played non redundant roles in primary tumorigenesis and lung-specific metastasis, such as integrin-linked kinase (Ilk), the transforming growth factorM-bM-^@M-^Sb family ligand inhibin bA, cyclooxygenase-2, and the epithelial cell adhesion molecule Tacstd2. It also contained gene signatures that predicted disease outcome in breast cancer patients. These results identify possible targets for treating breast cancer and lung metastases and provide a potential diagnostic tool for clinical use. All microarray experiments were performed by the personnel of the Genomics and Proteomics Unit of our Institution. Transcriptomal changes were determined using the Mouse Gene 1.0 ST arrays (Affymetrix). Two independent experiments were performed to identify the Vav2/Vav3-dependent transcriptome. In the first one, we compared the transcriptomes of Control, KD2/3(A) and KD2/3(B) to identify Vav family-dependent genes. In the second one, we compared the transcriptomes of KD2/3(A) and KD2/3+V2/3 cells. In all cases, total cellular RNA was extracted from three independent exponential cultures of the appropriate cell lines using the RNAeasy kit (Qiagen), quantified using 6000 Nano Chips (Agilent Technologies, Santa Clara, CA), and used (2.3 M-NM-<g/sample) to generated labeled cRNA probes according to the manufacturerM-bM-^@M-^Ys instructions (Affymetrix). Upon microarray hybridization, the raw data was normalized, filtered and analyzed with the Bioconductor software (www.bioconductor.com) using the Affy and Siggenes applications. Generation of knockdown cell lines. The shRNA-mediated knockdown of transcripts for Vav2 and Vav3 was carried out using already packaged Mission TRC lentiviral particles (Sigma-Aldrich) according to the manufacturerM-bM-^@M-^Ys protocol. The catalogue numbers and shRNA sequences yielding the greatest knockdown were clone number TRC0000097094 (5M-bM-^@M-^Y-CCGGGCCTGCATCTCTGGTTTAGATCTCGAGATCTAA ACCAGAGATGCAGGCTTTTTG-3M-bM-^@M-^Y) for the mouse Vav2 mRNA; TRC0000097124 (5M-bM-^@M-^Y-CCGGCCAGCATTTCTCGTCTTAAATCTCGAGATTTAA GACGAGAAATGCTGGTTTTTG-3M-bM-^@M-^Y) for the mouse Vav3 mRNA. Lentiviral particles containing the empty pLOK.1puro vector (Sigma-Aldrich) were used to generate the M-bM-^@M-^\ControlM-bM-^@M-^] 4T1 cells used in these experiments. Cells were incubated with lentiviral particles in the presence of 8 M-NM-<g/ml polybrene (Sigma), selected with puromycin (1 M-NM-<g/ml; Sigma), and used as either pools or isolated clones. Two clones of double Vav2;Vav3 knockdown cells (designated KD2/A(A) and KD2/3 (B)) were used in these experiments. Generation of rescued 4T1 cell lines. To generate the rescued KD2/3(A) cell line expressing both Vav2 and Vav3, cells were first infected with lentiviral particles produced from the pCCM33 vector (encoding wild type, HA-tagged Vav2) and then with lentiviral particles containing the pCQS1 vector (encoding wild type, Myc-tagged Vav3). Cells were then selected with hygromycin (present in the Vav2-encoding pCCM33 vector) and susbsequently sorted by flow cytometry to isolate GFP positive cells (which was expressed bicistronically from the same Vav3-encoding pCQS1 vector). A clone of double reconstituted cells was used in the microarray experiments and designated as KD2/3+V2/V3.
2012-10-03 | E-GEOD-33348 | biostudies-arrayexpress
Project description:The guanosine triphosphatases of the Rho and Rac subfamilies regulate protumorigenic pathways and are activated by guanine nucleotide exchange factors (Rho GEFs), which could be potential targets for anticancer therapies. We report that two Rho GEFs, Vav2 and Vav3, play synergistic roles in breast cancer by sustaining tumor growth, neoangiogenesis, and many of the steps involved in lung-specific metastasis. The involvement of Vav proteins in these processes did not correlate with Rac1 and RhoA activity or cell migration, implying the presence of additional biological programs. Microarray analyses revealed that Vav2 and Vav3 controlled a vast transcriptional program in breast cancer cells through mechanisms that were shared between the two proteins, isoform-specific or synergistic. Furthermore, the abundance of Vav regulated transcripts was modulated by Rac1-dependent and Rac1-independent pathways. This transcriptome encoded therapeutically targetable proteins that played non redundant roles in primary tumorigenesis and lung-specific metastasis, such as integrin-linked kinase (Ilk), the transforming growth factor–b family ligand inhibin bA, cyclooxygenase-2, and the epithelial cell adhesion molecule Tacstd2. It also contained gene signatures that predicted disease outcome in breast cancer patients. These results identify possible targets for treating breast cancer and lung metastases and provide a potential diagnostic tool for clinical use.
2012-10-03 | GSE33348 | GEO
Project description:Here, we report that the Rho GTPase activators Vav2 and Vav3 utilize a new, miR-200c-dependent mechanism that maintains the epithelial state by limiting the abundance of the Zeb2 transcriptional repressor in breast cancer cells. In parallel, Vav proteins engage an expression program that maintains epithelial cell traits in 3D culture. Depletion of Vav proteins triggers EMT in epithelioid breast cancer cells and, conversely, expression of constitutively active Vav2 restores both miR-200c expression and epithelial traits in mesenchymal breast cancer cells. In silico analyses suggest that the negative Vav-Zeb2 axis is operative in human luminal breast tumors.
2018-09-21 | GSE97385 | GEO
Project description:Upregulated Vav2 signaling induces a transcriptomic rewiring in epidermal stem cells
| PRJNA588436 | ENA
Project description:The Rho guanosine exchange factors Vav2 and Vav3 modulate epidermal stem cell function
| PRJNA750092 | ENA
Project description:It is known that Rho GTPases control different aspects of the biology of skin stem cells (SSCs). However, little information is available on the role of its upstream regulators under normal and tumorigenic conditions in this process. To address this issue, we have used here mouse models in which the activity of guanosine nucleotide exchange factors of the Vav subfamily has been manipulated using both gain- and loss-of-function strategies. These experiments indicate that Vav2 and Vav3 regulate the number, functional status, and responsiveness of hair follicle bulge stem cells. This is linked to gene expression programs related to the reinforcement of the SSC identity and the quiescent state. By contrast, Vav proteins promote transcriptomal programs associated with the identity and activation state of SSCs in cancer stem cells.
2022-05-07 | GSE180946 | GEO
Project description:This is a ordinary differential equation mathematical model describing the Rho GTPase cycle in which Rho GDP-dissociation inhibitors (RhoGDIs) inhibit the regulatory activities of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) by interacting with them directly as well as by sequestering the Rho GTPases. The model was constructed with the intent of analyzing the role of RhoGDIs in Rho GTPase signaling.
2024-09-02 | BIOMD0000000899 | BioModels