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Loss of Spry1 reduces growth of BRAFV600E-mutant cutaneous melanoma and improves response to targeted therapy

ABSTRACT: Loss of Spry1 reduces growth of BRAFV600E-mutant cutaneous melanoma and improves response to targeted therapy

PROVIDER: PRJEB32200 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR3284670_1.fastq.gz	Fastqsanger.gz
	ERR3284670_2.fastq.gz	Fastqsanger.gz
	ERR3284671_1.fastq.gz	Fastqsanger.gz
	ERR3284671_2.fastq.gz	Fastqsanger.gz
	ERR3284672_1.fastq.gz	Fastqsanger.gz

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Loss of Spry1 reduces growth of BRAFV600E-mutant cutaneous melanoma and improves response to targeted therapy

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

E-MTAB-7886

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

Dmrt1 maintains testicular immune homeostasis by activating Spry1 and inhibiting NF-κB signaling pathway [Spry1 KD RNA-Seq]

Project description:To explore the function of Spry1 in testis, we constructed a mouse model with testicular specific KD of Spry1 through seminiferous tubule transplantation

2023-09-01 | GSE212667 | GEO

Loss of Spry1 reduces growth of BRAF<sup>V600</sup>-mutant cutaneous melanoma and improves response to targeted therapy.

Project description:Mitogen-activated protein kinase (MAPK) pathway activation is a central step in BRAFV600-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 BRAFV600-mutant CM is still poorly defined. Here, we report that Spry1 knockdown (Spry1KO) in three BRAFV600-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 markers of epithelial-mesenchymal transition, 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 BRAFV600-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 the 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 BRAFV600-mutant CM by inducing the toxic effects of ERK-mediated signaling.

| S-EPMC7244546 | biostudies-literature

Pigment producing melanocytes as the cells of origin of BRAFV600E-induced mouse cutaneous melanoma

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

Role and function of SPRY1/2 in BCR-ABL1 driven pre-B cells

Project description:In order to investigate the function of SPRY1 and SPRY2 in ALL, we isolated bone marrow cells from Spry1 and 2 fl/fl mice and transformed them with BCR-ABL1. In a second transduction the BCR-ABL1 driven pre-B cells were transformed either with CRE-ERT2 or ERT2 (PMIP) and after 2 days of treatment with 4OH-Tamoxifen (0.5 micromolar) subjected to gene expression analysis. Two days after treatment with 4OH-Tamoxifen (0.5 micromolar) total RNA of Puromycin resistant cells was extracted and subjected to gene expression analysis.

2013-06-03 | E-GEOD-34834 | biostudies-arrayexpress

Role and function of SPRY1/2 in BCR-ABL1 driven pre-B cells

2013-06-03 | GSE34834 | GEO

Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis

Project description:Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis

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Tumor fibroblast-derived FGF2 regulates SPRY1 expression in esophageal tumor-infiltrating T cells and plays a role in T cell exhaustion

Project description:Using single-cell RNA sequencing, we found that exhausted T cells in esophageal cancer were more heterogeneous than previously clarified. We discovered that SPRY1 was notably enriched in two subsets of exhausted CD8+ T cells. When overexpressed, SPRY1 impaired T cell activation by interacting with CBL, which is a negative regulator of ZAP-70 tyrosine phosphorylation.

2023-08-21 | GSE156585 | GEO

Possible involvement of a MEG3-miR-21-SPRY1-NF-kB feedback loop in spermatogenic cells proliferation, autophagy and apoptosis

Project description:Non-obstructive azoospermia (NOA) is the most incurable male infertility with complex etiology. The molecular mechanism that determines the amount of spermatogenesis in NOA patients is still unclear. LncRNAs have been verified to associate with the regulation of spermatogenesis. However, the specific function and molecular mechanism remain to be confirmed. We use RNA-seq analysis for preliminary screening of different lncRNAs between NOA and normal male and find that MEG3 was upregulated in NOA testicular tissues and inhibit cell proliferation and promote cell autophagy and apoptosis in vitro and vivo. Through RNA immunoprecipitation (RIP), biotin pull-down assays and Dual Luciferase Reporter assays, MEG3 is proved to act as competing endogenous RNA of miR-21 and thus influence the SPRY1/ERK/mTOR signal pathway. In addition, SPRY1 positively regulates MEG3 through SPRY1/NF-κB/MEG3 feedback loop. These findings firstly demonstrate that LncRNA MEG3-miR-21-SPRY1-NF-κB acts as a new feedback loop leading to the occurrence of azoospermia through inhibiting the proliferation, promoting autophagy and apoptosis of spermatogenic cells, which provides a new target and theoretical basis for diagnosis and treatment of non-obstructive azoospermia.

2024-09-14 | GSE241326 | GEO

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