MicroRNA (miR)-211 loss promotes metabolic vulnerability and BRAF inhibitor sensitivity in melanoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA430713 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6497320.fastq.gz | Fastqsanger.gz | |||
| SRR6497321.fastq.gz | Fastqsanger.gz | |||
| SRR6497322.fastq.gz | Fastqsanger.gz | |||
| SRR6497323.fastq.gz | Fastqsanger.gz | |||
| SRR6497324.fastq.gz | Fastqsanger.gz |
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Project description:We report that miR-211 loss-of-function in the pigmented melanoma cell line SKMEL-28 slowed growth and invasion in vitro, inhibited phosphoinositol-3-kinase (PI3K) signaling, rendered these melanoma cells metabolically vulnerable by attenuating mitochondrial respiration and tricarboxylic acid (TCA) cycling and inhibited melanoma growth in vivo.
2019-01-02 | GSE109378 | GEO
Project description:Purpose: Identification of miRNAs that enable resistance to BRAF inhibitors in melanoma suggests a mechanism-based strategy to limit resistance and improve clinical outcomes. Methods: We generated A375 melanoma cells resistant to Vemurafenib (VMF) with the goal of investigating changes in miRNA expression patterns that might contribute to resistance. Results: Increased expression of miR-204-5p and miR-211-5p occurring in VMF-resistant cells was determined to impact VMF response.
2018-01-18 | GSE107576 | GEO
Project description:The clinical management of malignant melanoma remains a challenge because these tumors are intrinsically aggressive and prone to therapeutic resistance. MicroRNA (miR)-211 is an emerging melanoma oncogene. Melanoma metabolism adapts to promote survival, including in response to BRAFV600E inhibition, but how miR-211 participates in this process is unknown. Here, we generated miR-211 loss-of-function cell lines using CRISPR/Cas9 technology and show that miR-211 loss slowed growth and invasion in vitro, inhibited phosphoinositol-3-kinase signaling, and inhibited melanoma growth in vivo. miR-211 deficiency rendered melanoma cells metabolically vulnerable by attenuating mitochondrial respiration and tricarboxylic acid cycling. miR-211 was up-regulated by the BRAF inhibitor vemurafenib and in vemurafenib-resistant melanoma cells, with miR-211 loss rendering them more drug sensitive. miR-211 loss represents a "two-pronged" anticancer strategy by inhibiting both critical growth-promoting cell signaling pathways and rendering cells metabolically vulnerable, making it an extremely attractive and specific candidate combinatorial therapeutic target in melanoma.
| S-EPMC6309654 | biostudies-literature
Project description:miR-204-5p and miR-211-5p contribute to BRAF inhibitor resistance in melanoma
| PRJNA420730 | ENA
Project description:Melanoma treatment with the BRAF V600E inhibitor vemurafenib provides therapeutic benefits but the common emergence of drug resistance remains a challenge. We generated A375 melanoma cells resistant to vemurafenib with the goal of investigating changes in miRNA expression patterns that might contribute to resistance. Increased expression of miR-204-5p and miR-211-5p occurring in vemurafenib-resistant cells was determined to impact vemurafenib response. Their expression was rapidly affected by vemurafenib treatment through RNA stabilization. Similar effects were elicited by MEK and ERK inhibitors but not AKT or Rac inhibitors. Ectopic expression of both miRNA in drug-naïve human melanoma cells was sufficient to confer vemurafenib resistance and more robust tumor growth in vivo Conversely, silencing their expression in resistant cells inhibited cell growth. Joint overexpression of miR-204-5p and miR-211-5p durably stimulated Ras and MAPK upregulation after vemurafenib exposure. Overall, our findings show how upregulation of miR-204-5p and miR-211-5p following vemurafenib treatment enables the emergence of resistance, with potential implications for mechanism-based strategies to improve vemurafenib responses.Significance: Identification of miRNAs that enable resistance to BRAF inhibitors in melanoma suggests a mechanism-based strategy to limit resistance and improve clinical outcomes. Cancer Res; 78(4); 1017-30. ©2017 AACR.
| S-EPMC5815895 | biostudies-literature
Project description:Background Main drawback of BRAF/MEK inhibitors (BRAF/MEKi)-based targeted therapy in the management of BRAF- mutated cutaneous metastatic melanoma (MM) is the development of therapeutic resistance. We aimed to define in this context the specific role of mTORC2, a signaling complex defined by the presence of the essential RICTOR subunit and regarded as an oncogenic driver in several tumor types, including MM. Methods After analyzing the TCGA MM patients’ database to explore both overall survival and molecular signatures as a function of intra-tumor RICTOR levels, we investigated the effects of RICTOR downregulation in BRAF V600E MM cell lines on their response to BRAF/MEKi in vitro. We performed a proteomic screening to identify proteins modulated by changes in RICTOR expression and Seahorse analysis to evaluate the effects of RICTOR depletion on mitochondrial respiration. The combination of BRAFi with drugs targeting proteins and processes emerged in the proteomic screening was carried out on RICTOR-deficient cells in vitro and in a xenograft setting in vivo. Results We found that low RICTOR levels in MM correlate with an overall worse clinical outcome. GSEA of low- RICTOR tumors revealed a gene expression signature suggestive of activation of the mitochondrial Electron Transport Chain (ETC) energy producing pathway. RICTOR-deficient BRAF V600E cells are intrinsically tolerant to BRAFi/MEKi and anticipate the onset of resistance to BRAFi upon prolonged drug exposure. In RICTOR- depleted cells, both mitochondrial respiration and expression of nicotinamide phosphoribosyltransferase (NAMPT) are enhanced, while their pharmacological inhibition restores sensitivity to BRAFi. Conclusions Our work unveils a novel tumor suppressing role for mTORC2 in the responses of BRAF V600E melanoma cells to targeted therapy and identifies the NAMPT-ETC axis as a potential therapeutic vulnerability of low- RICTOR tumors. Importantly, our findings support the concept that the evaluation of intra-tumor RICTOR levels in MM has a prognostic value, and may help predicting the response of patients to targeted therapy.
2024-06-22 | PXD050614 | Pride
Project description:mRNA profiles generated from primary fibroblast upon treatment with miR-211, miR-302 or melanoma melanosomes. Abstract: Melanoma originates in the epidermis and enters the metastatic and lethal phase upon invasion into the dermis. However, the interactions between melanoma cells and the dermis prior to this invasion have been poorly studied. Here we uncover that melanoma cells directly affect the formation of the dermal tumor niche by microRNA (miRNA) trafficking prior to invading the dermis. Melanocytes, the cells of melanoma origin, are specialized in trafficking of pigment vesicles, termed melanosomes and, interestingly, melanoma cells retain this trafficking ability. In melanoma in-situ specimens, we found melanosome markers in distal fibroblasts prior to the invasion of melanoma cells into the dermis. Melanoma-derived melanosomes carry miRNAs into primary fibroblasts that trigger changes in the fibroblasts, including increased proliferation, migration, and expression of pro-inflammatory genes, all known features of cancer-associated fibroblasts (CAFs). Specifically, we found that melanosomal miRNA-211 directly targets IGF2R and leads to MAPK signaling activation in fibroblasts, which reciprocally encourages melanoma growth. Treatment of melanoma cells with a melanosome release-inhibitor prevented CAF formation. Since the first interaction of melanoma cells with blood vessels occurs in the dermis, our data suggest a promising opportunity to block melanoma cell invasion by preventing the formation of the dermal tumor niche. In the paper we showed the 10% of most differentially expressed mRNA upon miR-211, miR-320c and melanosomes treatment and overlap of 2000 downregulated mRNA upon miR-211 and melanosomes treatment with predicted target gene miR-211 and CAFs related genes Expresssion profiling was performed for primary fibroblasts transfected with miRNA-211 mimic and miRNA-320c mimic.
2016-08-09 | E-GEOD-72619 | biostudies-arrayexpress
Project description:mRNA profiles generated from primary fibroblast upon treatment with miR-211, miR-302 or melanoma melanosomes. Abstract: Melanoma originates in the epidermis and enters the metastatic and lethal phase upon invasion into the dermis. However, the interactions between melanoma cells and the dermis prior to this invasion have been poorly studied. Here we uncover that melanoma cells directly affect the formation of the dermal tumor niche by microRNA (miRNA) trafficking prior to invading the dermis. Melanocytes, the cells of melanoma origin, are specialized in trafficking of pigment vesicles, termed melanosomes and, interestingly, melanoma cells retain this trafficking ability. In melanoma in-situ specimens, we found melanosome markers in distal fibroblasts prior to the invasion of melanoma cells into the dermis. Melanoma-derived melanosomes carry miRNAs into primary fibroblasts that trigger changes in the fibroblasts, including increased proliferation, migration, and expression of pro-inflammatory genes, all known features of cancer-associated fibroblasts (CAFs). Specifically, we found that melanosomal miRNA-211 directly targets IGF2R and leads to MAPK signaling activation in fibroblasts, which reciprocally encourages melanoma growth. Treatment of melanoma cells with a melanosome release-inhibitor prevented CAF formation. Since the first interaction of melanoma cells with blood vessels occurs in the dermis, our data suggest a promising opportunity to block melanoma cell invasion by preventing the formation of the dermal tumor niche. In the paper we showed the 10% of most differentially expressed mRNA upon miR-211, miR-320c and melanosomes treatment and overlap of 2000 downregulated mRNA upon miR-211 and melanosomes treatment with predicted target gene miR-211 and CAFs related genes
2016-08-09 | GSE72619 | GEO
Project description:Despite increasing amounts of experimental evidence depicting the involvement of non-coding RNAs in cancer, the study of BRAFV600E-regulated genes has thus far focused mainly on protein-coding ones. Here, we identify and study the microRNAs that BRAFV600E regulates through the ERK pathway. By performing small RNA sequencing on A375 melanoma cells and a vemurafenib- resistant clone that was taken as negative control, we discover miR-204 and miR-211 as the miRNAs most induced by vemurafenib. We also demonstrate that, although belonging to the same family, these two miRNAs have distinctive features. miR-204 is under the control of STAT3 and its expression is induced in amelanotic melanoma cells, where it acts as an effector of vemurafenib’s anti-motility activity by targeting AP1S2. Conversely, miR-211, a known transcriptional target of MITF, is induced in melanotic melanoma cells, where it targets EDEM1 and consequently impairs the degradation of TYROSINASE (TYR) through the ER-associated degradation (ERAD) pathway. In doing so, miR-211 serves as an effector of vemurafenib’s pro-pigmentation activity. We also show that such an increase in pigmentation in turn represents an adaptive response that needs to be overcome using appropriate inhibitors in order to increase the ef cacy of vemurafenib. In summary, we unveil the distinct and context-dependent activities exerted by miR-204 family members in melanoma cells. Our work challenges the widely accepted “same miRNA family = same function” rule and provides a rationale for a novel treatment strategy for melanotic melanomas that is based on the combination of ERK pathway inhibitors with pigmentation inhibitors.
2017-03-26 | GSE94476 | GEO
Project description:We aimed to identify the potential proteins as a collateral vulnerability within PGC1a-suppressed BRAF-inhibitor resistant melanomas, and the potential mechanisms behind this including their abundancy and cellular distribution.
2023-06-09 | PXD041952 | Pride