Biology subjects

Chadourne, M.

Publications and source records attributed to Chadourne, M..

6 recordsLinked to original sources

bioRxiv2026

circPMS1-mediated LIM protein scaffolding promotes cytoskeletal remodeling and melanoma metastasis

Circular RNAs (circRNAs) have been implicated in diverse biological processes and diseases such as cancer; however, their functional roles in tumor biology remain incompletely understood. Here, we identify circPMS1 as an aberrantly upregulated, pro-metastatic circRNA in melanoma. Overexpression and silencing studies revealed that circPMS1 promotes migration and invasion of non-transformed melanocytes and melanoma cells, enhances metastasis in xenograft models, and drives spontaneous dissemination and lymph node metastases in a genetically engineered melanoma mouse model. circPMS1 pro-metastatic activity depends on its circularization and is mediated by a putative secondary structure spanning the back-splice junction and the canonical start codon of the linear PMS1 mRNA. Proteomic analysis identified LIM domain proteins, including ABLIM1, LMO7, and PDLIM7, as circPMS1-bound factors. Mechanistic studies demonstrate that circPMS1 scaffolds these LIM proteins, enhancing their association with actin filaments inducing focal adhesion and cytoskeletal remodeling. This remodeling is associated with RhoA activity, and inhibition of the RhoA pathway attenuates circPMS1-induced migration. Together, these findings establish circPMS1 as a pro-metastatic circRNA that drives melanoma progression by scaffolding LIM domain proteins and regulating cytoskeletal dynamics and cell motility.

Cancer Biology↗

bioRxiv2025

FRA1 drives melanoma metastasis through an actionable transcriptional network

Transcriptional dysregulation has emerged as a critical driver of melanoma progression, yet the molecular mechanisms governing this process and their potential as therapeutic targets remain inadequately characterized. Here, we identify FRA1 as a potent and actionable driver of melanoma metastasis. FRA1 enhanced both the initial seeding and subsequent outgrowth of metastatic lesions. Comprehensive multi-omics integration revealed transcriptional target genes of FRA1, with AXL, CDK6, and FSCN1 exhibiting increased expression in melanoma metastasis and a significant correlation with poor patient outcomes. Silencing AXL, CDK6, or FSCN1 abrogated FRA1-mediated invasion in vitro and reduced metastatic colonization. Furthermore, pharmacological inhibition of CDK6 and FSCN1, and to a lesser extent AXL, suppressed melanoma metastasis and prolonged overall survival. The expression of FRA1 and its target genes correlates with shortened survival across multiple cancer types, highlighting the broader clinical relevance of this pathway. This study unveils an actionable FRA1-mediated transcriptional network that drives cancer progression and metastasis, offering potential avenues for therapeutic interventions. SIGNIFICANCEFRA1 promotes melanoma metastasis by enhancing the expression of AXL, CDK6, and FSCN1 and this transcriptional network is associated with poor survival across several cancer types. Targeting these FRA1 effectors suppresses metastasis and extends survival, offering a therapeutic strategy for metastatic melanoma and potentially other aggressive cancers.

cancer biology↗

bioRxiv2024

CDH3-AS1 antisense RNA enhances P-cadherin translation and acts as a tumor suppressor in melanoma

Thousands of regulatory noncoding RNAs (ncRNAs) have been annotated; however, their functions in gene regulation and contributions to cancer formation remain poorly understood. To gain a better understanding of the influence of ncRNAs on gene regulation during melanoma progression, we mapped the landscape of ncRNAs in melanocytes and melanoma cells. Nearly half of deregulated genes in melanoma are ncRNAs, with antisense RNAs (asRNAs) comprising a large portion of deregulated ncRNAs. CDH3-AS1, the most significantly downregulated asRNA, overlaps the CDH3 gene, which encodes P-cadherin, a transmembrane glycoprotein involved in cell adhesion that was also reduced in melanoma. Overexpression of CDH3-AS1 increased cell aggregation and reduced xenograft tumor growth, mimicking the tumor-suppressive effects of CDH3. CDH3-AS1 interacted with CDH3 mRNA and enhanced P-cadherin protein levels. Interestingly, secondary structures at the CDH3 5 end regulated P-cadherin translation, and ribosome profiling revealed that CDH3-AS1 promotes ribosome occupancy at the CDH3 mRNA. Notably, ribosome occupancy was generally increased in mRNAs having cognate asRNA that are complementary to the 5UTR. Taken together, this study revealed the CDH3-AS1-mediated enhancement of P-cadherin translation, underscoring the broader potential of asRNAs as regulators of protein-coding genes and their role in diseases like melanoma.

molecular biology↗

bioRxiv2024

The small MAF transcription factor MAFG co-opts MITF to promote melanoma progression

Transcription factor deregulation potently drives melanoma progression by dynamically and reversibly controlling gene expression programs. We previously identified the small MAF family transcription factor MAFG as a putative driver of melanoma progression, prompting an in-depth evaluation of its role in melanoma. MAFG expression increases with human melanoma stages and ectopic MAFG expression enhances the malignant behavior of human melanoma cells in vitro, xenograft models, and genetic mouse models of spontaneous melanoma. Moreover, MAFG induces a melanoma phenotype switch from a melanocytic state to a more dedifferentiated state. Mechanistically, MAFG interacts with the lineage transcription factor MITF which is required for the pro-tumorigenic effects of MAFG. MAFG and MITF co-occupy numerous genomic sites and MAFG overexpression influences the expression of genes harboring binding sites for the MAFG[~]MITF complex. These results establish MAFG as a potent driver of melanomagenesis through dimerization with MITF and uncover an unappreciated mechanism of MITF regulation. Significance statementMITF is critically involved in melanoma progression and phenotype switching. We discovered that MAFG interacts with MITF to influence expression of MITF target genes and facilitate a shift toward a dedifferentiated melanoma cell state. This study demonstrates that MAFG promotes melanomagenesis by influencing MITF activity, an unappreciated mechanism of MITF regulation.

cancer biology↗

bioRxiv2023

The lipid phosphatase activity of PTEN dampens FRA1 expression via AKT/mTOR signaling to suppress melanoma

PTEN, a phosphatase frequently inactivated in melanoma, opposes PI3K/AKT/mTOR pathway activation. However, AKT- and mTOR-targeted therapies have so far yielded insufficient results in preclinical models and clinical trials of melanoma. We therefore examined whether PTEN suppresses melanoma through lipid phosphatase-independent functions or by opposing lipid phosphatase-dependent, AKT-independent pathways. Restoring different PTEN functions in PTEN-deficient cells or mouse models revealed that PTEN lipid phosphatase activity predominantly suppresses melanoma with minimal contribution from its protein phosphatase and scaffold functions. A drug screen highlighted the dependence of PTEN-deficient melanoma cells on the AKT/mTOR pathway. Moreover, activation of AKT was sufficient to overcome several aspects of PTEN-mediated melanoma suppression. Phosphoproteomics analysis of the PTEN lipid phosphatase activity identified the AP-1 transcription factor FRA1 as a downstream effector. PTEN regulates FRA1 translation via AKT/mTOR and FRA1 overexpression overcomes PTEN-mediated melanoma suppression. Our study affirms AKT as the key mediator of PTEN inactivation in melanoma and identifies an AKT/mTOR/FRA1 axis as a driver of melanomagenesis.

cancer biology↗

bioRxiv2021

Topaz1, an essential gene for murine spermatogenesis, down-regulates the expression of many testis-specific long non-coding RNAs.

Spermatogenesis involves coordinated processes, including meiosis, to produce functional gametes. We previously reported Topaz1 as a germ cell-specific gene highly conserved in vertebrates. Topaz1 knockout males are sterile with testes that lack haploid germ cells because of meiotic arrest after prophase I. To better characterize Topaz1-/- testes, we used RNA-sequencing analyses at two different developmental stages (P16 and P18). The absence of TOPAZ1 disturbed the expression of genes involved in microtubule and/or cilium mobility, which was consistent with testicular histology showing the disruption of microtubules and centrosomes. Moreover, a quarter of P18 dysregulated genes are long non-coding RNAs (lncRNAs), and three of them are testis-specific and located in spermatocytes, their expression starting between P11 and P15. The suppression of one of them, 4939463O16Rik, did not alter fertility although sperm parameters were disturbed and sperm concentration fell. The transcriptome of P18-4939463O16Rik-/- testes was altered and the molecular pathways affected included microtubule-based processes, the regulation of cilium movement and spermatogenesis. The absence of TOPAZ1 protein or 4930463O16Rik produced the same enrichment clusters in mutant testes despite a contrasted phenotype on male fertility. In conclusion, TOPAZ1 appeared to stabilize the expression of numerous lncRNAs. Its suppression is not essential for fertility but required during the terminal differentiation of male gametes. Author SummaryThe Topaz1 gene was initially characterized during the initiation of meiosis in the sheep fetal ovary. In order to determine its function, a KO of the murine gene was performed. In this species, only males were sterile and spermatogenesis was blocked before the first meiotic division. Here, we show that cytoskeletal elements are markedly disturbed in mutant testes, indicating that these elements play an important function in spermatogenesis. While the mitotic spindle of spermatogonia was normal, the meiotic spindle of spermatocytes was hemi-spindle-shaped and the homologous chromosome pairs could position themselves on the equatorial plate. In addition, lncRNAs account for 25% of genes whose expression in testes varies significantly in the absence of Topaz1. This suggests a key role for these factors in spermatogenesis. Largely testis-specific, they may be involved in spermatogenesis and play a more or less critical role in mouse fertility, which probably also depends on their redundancies.

developmental biology↗