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| Status |
Public on Dec 29, 2021 |
| Title |
Blockade of the pro-fibrotic reaction mediated by the miR-143/-145 cluster enhances the responses to targeted therapy in melanoma |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Expression profiling by array
Non-coding RNA profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
Refer to individual Series
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| |
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| Citation(s) |
35156321 |
| Submission date |
Apr 12, 2021 |
| Last update date |
Mar 15, 2022 |
| Contact name |
Kevin Lebrigand |
| Organization name |
IPMC/CNRS
|
| Lab |
Functional Genomics Platform of Nice-Sophia-Antipolis, France.
|
| Street address |
660 route des lucioles
|
| City |
Valbonne - Sophia-Antipolis |
| ZIP/Postal code |
06560 |
| Country |
France |
| |
|
| Platforms (3) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
| GPL21185 |
Agilent-072363 SurePrint G3 Human GE v3 8x60K Microarray 039494 [Probe Name Version] |
| GPL26167 |
PromethION (Homo sapiens) |
|
| Samples (12)
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| This SuperSeries is composed of the following SubSeries: |
| GSE171880 |
Impact of miR-143-3p and miR-145-5p overexpression on human M238P melanoma cells |
| GSE171881 |
RNA-Seq analysis of human M238P melanoma cells transduced with a lentivirus expressing the miR-143/145 cluster or a control lentivirus |
| GSE171882 |
RNA-Seq analysis (long-reads) of human parental M238P and BRAF inhibitors-resistant M238R melanoma cells |
|
| Relations |
| BioProject |
PRJNA721319 |
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