Loss of neural crest-associated gene FOXD1 impairs melanoma invasion and migration via RAC1B downregulation
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ABSTRACT:
PROVIDER: PRJNA438110 | ENA |
REPOSITORIES: ENA
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Project description:Recent studies suggest that malignant melanoma heterogeneity includes subpopulations of cells with features of multipotent neural crest (NC) cells. Zebrafish and mouse models have shown that reactivation of neural crest-specific pathways determines the invasiveness of melanoma cells. In this study, we show that the neural crest-associated transcription factor FOXD1 plays a key role in invasion and migration capacity of metastatic melanomas both in vivo and in vitro. Gene expression profiling analysis identified on one hand, an upregulation of FOXD1 in NC and melanoma cells, and on the other hand, a downregulation of several genes related to cell invasion in FOXD1 knockdown cells, including MMP9 and RAC1B. Furthermore, we demonstrate that knockdown of RAC1B a tumor-specific isoform of RAC1, significantly impaired cell migration and invasion in melanoma and could abrogate enhanced invasiveness induced by FOXD1 overexpression. We conclude that FOXD1 may influence invasion and migration via indirect regulation of MMP9 and RAC1B alternative splicing in melanoma cells.
2018-08-31 | GSE111766 | GEO
Project description:Cell senescence is a driver of various aging-associated disorders including osteoarthritis. Here, we identified a critical role for Yes-associated protein (YAP), a major effector of Hippo signaling, in maintaining a younger state of human mesenchymal stem cells (MSCs) and ameliorating osteoarthritis in mice. Targeted knockout of YAP in hMSCs resulted in premature cellular senescence. Mechanistically, YAP interacted with TEA domain transcriptional factor (TEAD) to activate forkhead box D1 (FOXD1) expression. YAP deficiency led to the downregulation of FOXD1, a geroprotective protein. In turn, overexpression of YAP or FOXD1 rejuvenated aged hMSCs. Moreover, intra-articular administration of lentiviral vectors encoding YAP or FOXD1 attenuated the development of osteoarthritis in mice. Collectively, our findings reveal YAP-FOXD1, a novel aging-associated regulatory axis, as a potential therapeutic target for gene therapy to alleviate osteoarthritis.
2019-02-17 | GSE110268 | GEO
Project description:Neural crest cells are both highly migratory and significant to vertebrate organogenesis. However, the signals that regulate neural crest cell migration remain unclear. Here, we test the function of DAN, a BMP antagonist we detected by analysis of chick cranial mesoderm. Our analysis shows that, prior to neural crest cell exit from the hindbrain, DAN is expressed in the mesoderm, then it becomes absent along cell migratory pathways. Cranial neural crest and metastatic melanoma cells avoid DAN protein stripes in vitro. Addition of DAN reduces the speed of migrating cells, in vivo and in vitro respectively. In vivo loss-of-function of DAN results in enhanced neural crest cell migration by increasing speed and directionality. Computer model simulations support the hypothesis that DAN restrains cell migration by regulating cell speed. Taken together, our results identify DAN as a novel factor that inhibits uncontrolled neural crest and metastatic melanoma invasion and promotes collective migration in a manner consistent with inhibition of BMP signaling.
2017-08-07 | GSE101746 | GEO
Project description:Metastatic melanoma is the most aggressive skin cancer and associated with a poor prognosis. Targeted therapy is one of the most important treatments for patients with BRAFV600E-mutated advanced melanoma. However, the development of resistance to this treatment compromises its therapeutic success. Increasing evidence has indicated that NC-associated genes play important roles in tumor progress and drug resistance. Our previous study showed that FOXD1 is a neural crest (NC)-associated gene that has high expression levels both in NC cells and melanoma and that it could regulate melanoma migration and invasion. Here, we found that the FOXD1-CTGF axis is important for melanoma resistance. The connective tissue growth factor (CTGF) was identified as a direct downstream factor of FOXD1 using microarray assay. In detail, when we compared the microarray data from FOXD1 OE and control groups, we found that the expression level of CTGF was also higher in FOXD1 OE cells (FC=1.97).
2021-03-29 | GSE162973 | GEO
Project description:It remains unclear how the ectopic expression of defined transcription factors induces dynamic changes in gene expression profiles that establish a pluripotent state during direct cell reprogramming. In the present study, we first identified a temporal gene expression program during the reprogramming process. Promoter analyses then predicted the role of two forkhead box transcription factors, Foxd1 and Foxo1, as mediators of the gene expression program. Knockdown of Foxd1 or Foxo1 reduced the number of induced pluripotent stem cells (iPSCs). The knockout of Foxd1 prevented the downstream transcription program, including the expression of reprogramming marker genes. Interestingly, the expression level of Foxd1 was also transiently increased in a small population of cells in the middle stage of reprogramming. The presence or absence of Foxd1 expression in this stage was correlated with a future cell fate as iPSCs or non-reprogrammed cells. These results suggest that Foxd1 is a mediator and indicator of the successful progression of the gene expression program in cell reprogramming. Mouse embryonic fibroblasts (MEFs) of Foxd1+/+, Foxd1+/- or Foxd1-/- were infected with retroviruses encoding the three transcription factors (Oct4, Sox2 and Klf4) at day 0 and sampled at day 8.
2014-01-11 | E-GEOD-51179 | biostudies-arrayexpress
Project description:It remains unclear how the ectopic expression of defined transcription factors induces dynamic changes in gene expression profiles that establish a pluripotent state during direct cell reprogramming. In the present study, we first identified a temporal gene expression program during the reprogramming process. Promoter analyses then predicted the role of two forkhead box transcription factors, Foxd1 and Foxo1, as mediators of the gene expression program. Knockdown of Foxd1 or Foxo1 reduced the number of induced pluripotent stem cells (iPSCs). The knockout of Foxd1 prevented the downstream transcription program, including the expression of reprogramming marker genes. Interestingly, the expression level of Foxd1 was also transiently increased in a small population of cells in the middle stage of reprogramming. The presence or absence of Foxd1 expression in this stage was correlated with a future cell fate as iPSCs or non-reprogrammed cells. These results suggest that Foxd1 is a mediator and indicator of the successful progression of the gene expression program in cell reprogramming.
2014-01-11 | GSE51179 | GEO
Project description:Forkhead transcription factors are essential for diverse processes in early embryonic development and organogenesis. Foxd1 is required during kidney development and its inactivation results in failure of nephron progenitor cell differentiation. Foxd1 is expressed in interstitial cells adjacent to nephron progenitor cells, suggesting an essential role for the progenitor cell niche in nephrogenesis. To better understand how cortical interstitial cells in general, and FOXD1 in particular, influence the progenitor cell niche, we examined the differentiation states of two progenitor cell subtypes in Foxd1-/- tissue. We found that while nephron progenitor cells are retained in a primitive CITED1-expressing compartment, cortical interstitial cells prematurely differentiate. To identify pathways regulated by FOXD1, we used microarray analysis and screened for target genes by comparison of Foxd1 null and wild type tissues. We chose the E14.5 timepoint because at this stage nephron differentiation is present in wild type kidneys but absent from Foxd1 null kidneys. We examined genes that were upregulated or downregulated in the Foxd1 null compared to wild type.
2013-11-14 | GSE52354 | GEO
Project description:Forkhead transcription factors are essential for diverse processes in early embryonic development and organogenesis. Foxd1 is required during kidney development and its inactivation results in failure of nephron progenitor cell differentiation. Foxd1 is expressed in interstitial cells adjacent to nephron progenitor cells, suggesting an essential role for the progenitor cell niche in nephrogenesis. To better understand how cortical interstitial cells in general, and FOXD1 in particular, influence the progenitor cell niche, we examined the differentiation states of two progenitor cell subtypes in Foxd1-/- tissue. We found that while nephron progenitor cells are retained in a primitive CITED1-expressing compartment, cortical interstitial cells prematurely differentiate. To identify pathways regulated by FOXD1, we used microarray analysis and screened for target genes by comparison of Foxd1 null and wild type tissues. We chose the E14.5 timepoint because at this stage nephron differentiation is present in wild type kidneys but absent from Foxd1 null kidneys. We examined genes that were upregulated or downregulated in the Foxd1 null compared to wild type. Embryonic kidneys were harvested from Foxd1-/- and wild type littermates from three E14.5 litters. Three biological replicates were generated per genotype, each containing two non-littermate kidney pairs. Sex of embryos was not determined.
2013-11-14 | E-GEOD-52354 | biostudies-arrayexpress
Project description:FOXD1 regulates proliferation of clear cell renal cell carcinoma (ccRCC) cells, and ccRCC cells in which FOXD1 has been inactivated do not form tumors efficiently in an animal model. Reproducing growth inhibition in tumor cells by inhibiting FOXD1 pathways presents an possible therapeutic approach for ccRCC and other cancers. We have established an analysis strategy to identify FOXD1-regulated target pathways that may be therapeutically tractable and compounds that modulate these pathways were selected for testing.
2022-08-01 | GSE210145 | GEO
Project description:Neural crest cells migrate throughout the embryo, but how cells move in a directed and collective manner has remained unclear. Here, we perform the first single-cell transcriptome analysis of cranial neural crest cell migration at three progressive stages in chick and identify and establish hierarchical relationships between cell position and time-specific transcriptional signatures. We determine a novel transcriptional signature of the most invasive neural crest Trailblazer cells that is consistent during migration and enriched for approximately 900 genes. Knockdown of several Trailblazer genes shows significant but modest changes to total distance migrated. However, in vivo expression analysis by RNAscope and immunohistochemistry reveals some salt and pepper patterns that include strong individual Trailblazer gene expression in cells within other subregions of the migratory stream. These data provide new insights into the molecular diversity and dynamics within a neural crest cell migratory stream that underlie complex directed and collective cell behaviors.
2017-12-19 | GSE108221 | GEO