Biology subjects

Wessely, A.

Publications and source records attributed to Wessely, A..

3 recordsLinked to original sources

bioRxiv2025

Network-based analysis reveals microRNA regulation of oncogenic pathways in SOX10-depleted uveal melanoma

SOX10 is essential for melanocyte development and maintenance and plays a critical role in uveal melanoma (UM) initiation and progression. While SOX10s transcriptional regulation of protein-coding genes is well characterized, its role on microRNA (miRNA) regulatory landscape in UM remains unexplored. Here, we employed network-based modeling to systematically characterize miRNA regulatory functions following SOX10 depletion in UM. First, we profiled mRNA and miRNA expression levels in SOX10 wild-type and knockdown UM cells. Then, we integrated the transcriptomic data, a UM network, and a Bayesian model to quantify miRNAs regulatory activities and identify key miRNAs. Subsequently, we employed pathway enrichment analysis combined with literature mining to elucidate the functional roles of identified miRNAs through their target genes and associated signaling pathways in UM. We identified 17 miRNAs that show significant changes in regulatory activities following SOX10 knockdown in UM cells. These miRNAs regulate the expression of genes involved in cancer hallmark pathways, including cell cycle progression, mTORC1 signaling, and fatty acid metabolism. Notably, miR-34a, miR-25, miR-186, and miR-211 have tumor-suppressive potential by targeting genes involved in UM progression and metastasis. Our results suggested that SOX10 depletion in UM can activate tumor-suppressive mechanisms through regulating miRNAs.

cancer biology↗

bioRxiv2025

A computational SOX10 network-based selection strategy to identify new drug targets in uveal melanoma

Uveal melanoma (UM) is the most common intraocular malignancy in adults. In contrast to cutaneous melanoma (CM), effective treatment options for metastatic UM are limited. The transcription factor SOX10 is crucial for CM initiation and survival, making it an interesting candidate for new targeted therapies, but its relevance in UM was unclear. We found that SOX10 was widely expressed in UM and essential for proliferation, cell cycle progression, and survival. The effects were partially mediated by SOX10-related genes including MITF, highlighting high addiction of UM to the SOX10-MITF axis. Additionally, SOX10 knockdown induced massive transcriptomic changes. Due to a lack of specific inhibitors of SOX10 and MITF, a computational approach was used to identify druggable targets by curating a UM-specific protein interaction network to search for candidates downregulated upon SOX10 inhibition. Thereby, the E2F transcription factor family was identified and their potential as druggable target candidates in UM was confirmed using the pan-E2F inhibitor HLM006474, resulting in cell cycle arrest and apoptosis. Taken together, SOX10 is crucial for UM survival and SOX10-associated proteins may serve as promising targets for developing new therapeutic strategies in UM.

cancer biology↗

bioRxiv2024

SOX10 and microRNAs: decoding their interplay in regulating melanoma plasticity

Recent studies show that the dysregulation of the transcription factor SOX10 is essential for development and progression of melanoma. MicroRNAs (miRNAs) can regulate the expression of transcription factors at the post-transcriptional level. The interactions between SOX10 and its targeting miRNAs form network motifs such as feedforward and feedback loops. Such motifs can result in non-linear dynamics in gene expression levels, therefore playing a crucial role in regulating tumor proliferation and metastasis as well as tumors responses to therapies. Here, we reviewed and discussed the intricate interplay between SOX10 and miRNAs in melanoma biology including melanogenesis, phenotype switch, and therapy resistance. Additionally, we investigated the gene regulatory interactions in melanoma, identifying crucial network motifs that involve both SOX10 and miRNAs. We also analyzed the expression levels of the components within these motifs. From a control theory perspective, we explained how these dynamics are linked to the phenotypic plasticity of melanoma cells. In summary, we underscored the importance of employing a data-driven network biology approach to elucidate the complex regulatory mechanisms and identify driver network motifs within the melanoma network. This methodology facilitates a deeper understanding of the regulation of SOX10 by miRNAs in melanoma. The insight gained could potentially contribute to the development of miRNA-based treatments for SOX10, thereby enhancing the clinical management of this malignancy.

systems biology↗