Loss of Spry1 reduces growth of BRAFV600E-mutant cutaneous melanoma and improves response to targeted therapy
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PROVIDER: PRJEB32200 | ENA |
REPOSITORIES: ENA
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Project description:Mitogen-activated protein kinase (MAPK) pathway activation is a central step in BRAFV600E-mutant cutaneous melanoma (CM) pathogenesis. In the last years, Spry1 has been frequently described as an upstream regulator of MAPK signaling pathway. However, its specific role in BRAFV600E-mutant CM is still poorly defined. Here, we report that Spry1 knockdown (Spry1KO) in three BRAFV600E-mutant CM cell lines markedly induced cell cycle arrest and apoptosis, repressed cell proliferation in vitro, and impaired tumor growth in vivo. Furthermore, our findings indicated that Spry1KO reduced the expression of several EMT-markers, such as MMP-2 both in vitro and in vivo. These effects were associated with a sustained and deleterious phosphorylation of ERK1/2. In addition, p38 activation along with an increase in basal ROS levels were found in Spry1KO clones compared to parental CM cell lines, suggesting that BRAFV600E-mutant CM may restrain the activity of Spry1 to avoid oncogenic stress and to enable tumor growth. Consistent with this hypothesis, treatment with the BRAF inhibitor (BRAFi) vemurafenib down-regulated Spry1 levels in parental CM cell lines, indicating that Spry1 expression is sustained by MAPK/ERK signaling pathway in a positive feedback loop that safeguards cells from the potentially toxic effects of ERK1/2 hyperactivation. Disruption of this feedback loop rendered Spry1KO cells more susceptible to apoptosis and markedly improved response to BRAFi both in vitro and in vivo, as a consequence of the detrimental effect of ERK1/2 hyperactivation observed upon Spry1 abrogation. Therefore, targeting Spry1 might offer a treatment strategy for BRAFV600E-mutant CM by inducing the toxic effects of ERK-mediated signaling.
2020-05-26 | E-MTAB-7886 | biostudies-arrayexpress
Project description:Loss of Spry1 reduces growth of BRAFV600E-mutant cutaneous melanoma and improves response to targeted therapy
2019-08-08 | E-MTAB-7886 | ExpressionAtlas
Project description:To investigate whether cutaneous melanoma originates from a resident adult melanocyte stem cell (MSC) or a mature melanocyte, we created a model that recapitulates key histopathological features of human melanomagenesis by inducing a BRafV600E-driven melanomagenic program in interfollicular (IF) melanocytes located in mouse tails. To this end, we sequenced the transcriptome of FACS-sorted individual IFE reporter-positive cells from BRaf/Pten/tdTomato mice, the tails of which had been painted with 4-HT for 31 and 72 days, respectively. These time points were chosen as melanoma cells are exclusively found in the IF epidermis at day 31 (d31) and in both epidermis and dermis at day 72 (d72). Normal IF melanocytes from Tyr::CreERT2/+; ROSA26RLSL-tdTomato/+ were also isolated and profiled These data indicated that loss of differentiation markers occurs in a subset of targeted epidermal melanoma cells before the onset of dermal invasion and that this event may, at least partly, be a consequence of induction of Zeb1 expression.
2017-11-16 | GSE100607 | GEO
Project description: Not available
| S-EPMC3638050 | biostudies-literature
Project description: Not available
| S-EPMC7244546 | biostudies-literature
Project description:Background: Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent form of skin cancer, showing a rapid increasing incidence worldwide. Although most cSCC can be cured by surgery, a sizeable number of cases are diagnosed at advanced stages, with local invasion and distant metastatic lesions. In the skin, neurotrophins (NTs) and their receptors (CD271 and Trk) form a complex network regulating epidermal homeostasis. Recently, several works suggested a significant implication of NT receptors in cancer. However, CD271 functions in epithelial tumors are controversial and its precise role in cSCC is still to be defined. Methods: Spheroids from cSCC patients with low-risk (In situ or Well-Differentiated cSCC) or high-risk tumors (Moderately/Poorly Differentiated cSCC), were established to explore histological features, proliferation, invasion abilities, and molecular pathways modulated in response to CD271 overexpression or activation in vitro. The effect of CD271 activities on the response to therapeutics was also investigated. The impact on the metastatic process and inflammation was explored in vivo and in vitro, by using zebrafish xenograft and 2D/3D models. Results: Our data proved that CD271 is upregulated in Well-Differentiated tumors as compared to the more aggressive Moderately/Poorly Differentiated cSCC, both in vivo and in vitro. We demonstrated that CD271 activities reduce proliferation and malignancy marker expression in patient-derived cSCC spheroids at each tumor grade, by increasing neoplastic cell differentiation. CD271 overexpression significantly increases cSCC spheroid mass density, while it reduces their weight and diameter, and promotes a major fold-enrichment in differentiation and keratinization genes. Moreover, both CD271 overexpression and activation decrease cSCC cell invasiveness in vitro. A significant inhibition of the metastatic process by CD271 was observed in a newly established zebrafish cSCC model. We found that the recruitment of leucocytes by CD271-overexpressing cells directly correlates with tumor killing and this finding was further highlighted by monocyte infiltration in a THP-1-SCC13 3D model. Finally, CD271 activity synergizes with Trk receptor inhibition, by reducing spheroid viability, and significantly improves the outcome of photodynamic therapy (PTD) or chemotherapy in spheroids and zebrafish. Conclusion: Our study provides evidence that CD271 could prevent the switch between low to high-risk cSCC tumors. Because CD271 contributes to maintaining active differentiative paths and favors the response to therapies, it might be a promising target for future pharmaceutical development.
2023-08-22 | GSE178845 | GEO
Project description:Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis
| PRJNA540690 | ENA
Project description:Gene expression profiling was performed to access the changes in gene expression in melanomas from Pdk1-inactivated Brafv600E::Pten-/- mice. The expression profiles of the BrafV600E::Pten-/-::Pdk1-/- were compared to the BrafV600E::Pten-/-::Pdk+/+ genotypes. The analysis has identified several important signaling pathways in Pdk1-dependent melanomagenesis. Melanoma tumors from the BrafV600E::Pten-/-::Pdk1+/+ and BrafV600E::Pten-/-::Pdk1-/- genotypes were harvested and mRNA from each group was pooled to enable four biologically replicates analysis.
2013-09-17 | E-GEOD-42187 | biostudies-arrayexpress
Project description: Not available
| S-EPMC4673141 | biostudies-literature
Project description:Transcriptional profiling of mouse NIH3T3 cells comparing control NIH3T3 cells transfected with a pEFm6-BRAF with cells transfected with pEFm6-BRAFV600E. Goal was to determine the effects of BRAFV600E gene transfection on global mouse NIH3T3 cells gene expression.
2017-01-01 | GSE90589 | GEO