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Blockade of the pro-fibrotic reaction mediated by the miR-143/-145 cluster enhances the responses to targeted therapy in melanoma

ABSTRACT: Blockade of the pro-fibrotic reaction mediated by the miR-143/-145 cluster enhances the responses to targeted therapy in melanoma

PROVIDER: PRJNA721319 | ENA |

REPOSITORIES: ENA

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Blockade of the pro-fibrotic reaction mediated by the miR-143/-145 cluster enhances the responses to targeted therapy in melanoma

Project description:Lineage dedifferentiation towards a mesenchymal-like state displaying myofibroblast and fibrotic features is a common mechanism of adaptive and resistance to targeted therapy in melanoma. Here we show that the anti-fibrotic drug Nintedanib is active to normalize the fibrous ECM network, enhance the efficacy of MAPK-targeted therapy and delay tumor relapse in a pre-clinical model of melanoma. Acquisition of this resistant phenotype and its reversion by Nintedanib pointed to miR-143/-145 pro-fibrotic cluster as a driver of this mesenchymal-like phenotype. Upregulation of the miR-143/-145 cluster under BRAFi/MAPKi therapy was observed in melanoma cells in vitro and in vivo and was associated with an invasive/undifferentiated profile. The 2 mature miRNAs generated from this cluster, miR-143-3p and miR-145-5p collaborated to mediate transition towards a drug resistant undifferentiated mesenchymal-like state by targeting Fascin actin-bundling protein 1 (FSCN1), modulating the dynamic crosstalk between the actin cytoskeleton and the ECM through the regulation of focal adhesion dynamics and mechanotransduction pathways. Our study brings insights into a novel miRNA-mediated regulatory network that contributes to non-genetic adaptive drug resistance and provides proof-of-principle that preventing MAPKi-induced pro-fibrotic stromal response is a viable therapeutic opportunity for patients on targeted therapy.

2021-12-29 | GSE171883 | GEO

The mir-143-145 cluster plays a pro-tumorigenic role in lung adenocarcinoma by promoting neoangiogenesis

Project description:A growing body of literature has proposed cell-autonomous tumor suppressor functions for the mir-143~145 cluster in a variety of human cancers, including lung adenocarcinoma, and has reported therapeutic benefits of delivering mir-143 and mir- 145 to tumors. In contrast to these studies, we found that depletion or forced expression of mir-143 and mir-145 in an autochthonous mouse model of lung adenocarcinoma did not affect tumor development. Surprisingly, we observed that loss of mir-143~145 from the tumor microenvironment significantly reduced tumor burden, indicating a non-cell- autonomous role for these miRNAs in promoting tumorigenesis. By examining the expression patterns of different cell populations isolated in vivo from tumor-bearing lungs using an integrated computational approach, we identified a role for mir-145 in stimulating the proliferation of endothelial cells by downregulating an inhibitory kinase, Camk1d, which prevents mitotic entry. As a consequence, tumors in mir-143~145- deficient animals exhibited diminished hallmarks of neo-angiogenesis, increased apoptosis and their expansion appeared limited by the tumor’s ability to co-opt the alveolar vasculature. These findings show that expression of the mir-143~145 cluster in the tumor stroma promotes rather than suppresses tumorigenesis and cautions against the use of these miRNAs as agents in cancer therapeutics.

2016-05-21 | GSE71877 | GEO

Mouse ureter: wild type vs miR-143/145 knock out

Project description:mRNA profiling of mouse ureters comparing wild-type ureter vs. ureters from mice having whole body deletion of miR-143 and miR-145 which results in abnormal ureter peristalsis and hydronephrosis We used microarrays to detail the global program of gene expression in wild-type and miR-143/145-deficient ureters which revealed dysregulation of genes linked to smooth muscle morphology and function. Two condition experiment: wild type vs miR-143/145 KO; biological replicates: individual mice - 2 wild type, 2 mutant. One replicate per array.

2014-10-08 | E-GEOD-58274 | biostudies-arrayexpress

Mouse ureter: wild type vs miR-143/145 knock out

2014-10-08 | GSE58274 | GEO

RNA-Seq analysis of human M238P melanoma cells transduced with a lentivirus expressing the miR-143/145 cluster or a control lentivirus

Project description:To assess the transcriptomic response associated with upregulation of the miR-143/-145 cluster, BRAFV600E mutant human melanoma cells M238P cells were transduced for stable expression of miR-143/145 cluster or with a control vector. Forty-eight hours after transduction, cells were treated with 1 μg/mL of puromycin for one week. RNA samples were then harvested. Two independent experiments were carried out.

2021-12-29 | GSE171881 | GEO

rs41291957 alters secondary RNA structure of the human pri-miR-143/145

Project description:Purpose: To evaluate whether the single nucleotide polimorphsim rs41291957, located in the pri-miR-143/145, influences the primary RNA secondary structure. Methods: In vitro transcription and folding for the pri-miR-143/145 carrying the WT allele (G) or the mutated one (A) was carried out. The RNAs were then subjected to RNAseI treatement for 30 minutes and RNA seq performed on the digested nucleic acids. Results: Using an optimized data analysis workflow for small RNAs, we mapped the sequence reads on the human pri-miR-143/145 carrying the G- or A-allele. We observed an increase of small reads (<60bps) for the A-allele and a different profile of read enrichement between the digested G- and A-allele RNA, indicating the difference in secondary structure.

2021-07-15 | GSE180017 | GEO

Analysis of miR-143/145 wild-type and null mouse intestinal myofibroblasts before and after LPS stimulation

Project description:In a series of mouse genetic studies, we concluded that miR-143/145 expression in intestinal subepithelial myofibroblasts (ISEMFs) promotes epithelial regeneration after DSS-mediated injury in the colon. This experiment aims to identify miR-143/145 target genes that are involved in this function. We generated primary ISEMFs from wildtype and miR-143/145 null mouse colons and analyzed their gene expression profile. We further subjected ISEMFs to LPS treatment, in order to measure gene expression changes that are only revealed after inflammatory stress.

2014-05-22 | GSE55651 | GEO

Blockade of the pro-fibrotic reaction mediated by the miR-143/-145 cluster enhances the responses to targeted therapy in melanoma

Project description: Not available

| S-SCDT-EMM-2021-15295 | biostudies-other

Analysis of miR-143/145 wild-type and null mouse intestinal myofibroblasts before and after LPS stimulation

2014-05-22 | E-GEOD-55651 | biostudies-arrayexpress

Mice heart: wild-type mice vs. alpha MHC/mir-143/145 transgenic mice

Project description:Transcriptional profilings of the mouse heart obtained from control (wild-type) and alpha MHC/mir-143/145 transgenic mouse line 9 and 19.

2019-04-01 | GSE112355 | GEO

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