Lopez-Cerdan, A. | bioRxiv Science

bioRxiv2024

Unveiling common transcriptomic features between melanoma brain metastases and neurodegenerative diseases

Melanoma represents a critical clinical challenge due to its high incidence rates and unfavorable clinical outcomes. This type of skin cancer presents unique adaptability to the brain microenvironment, but its underlying molecular mechanisms are poorly understood. To further characterize its tumor neurobiology, we explore the relation between the transcriptional profiles of melanoma brain metastasis (MBM) and the neurodegenerative diseases Alzheimers disease, Parkinsons disease, and multiple sclerosis. Through an in silico approach, we unveiled the neurodegenerative signature of MBM when compared to melanoma non-brain metastasis (53 dysregulated genes enriched in 11 functional terms) and to non tumor-bearing brain controls (195 dysregulated genes, mostly involved in development and cell differentiation, chromatin remodeling and nucleosome organization, and translation). Two genes, ITGA10 and DNAJC6, emerged as key potential markers, as they are dysregulated in both scenarios. Lastly, we developed a user-friendly web tool (https://bioinfo.cipf.es/metafun-mbm/) as an open source, so that any user can interactively delve into the results.

cancer biology↗

bioRxiv2023

Novel diagnosis and progression microRNA signatures in melanoma

Melanoma incidence is rising, and accurate risk stratification remains challenging because of the molecular heterogeneity underlying disease progression. Specifically, the transition from benign nevi to malignant melanoma and the acquisition of the aggressive ulcerated phenotype represent critical barriers in clinical management that require novel biomarkers. In addition, there is a critical need for novel biomarkers to identify patients with primary melanoma who, despite complete surgical resection, remain at high risk of recurrence and would benefit from adjuvant therapy. We applied an integrative systems biology approach to decipher the miRNA-dependent regulatory architecture of melanoma. Following PRISMA guidelines, we conducted a robust meta-analysis of six independent transcriptomic studies, overcoming inter-study heterogeneity. This was coupled with network inference algorithms to construct validated miRNA-mRNA interactomes and identify dynamic functional modules. In the diagnostic scenario, we identified a consensus signature of 24 miRNAs. Network topology analysis revealed hsa-miR-142-5p as a master regulator that orchestrates the dismantling of the Oncogene-Induced Senescence (OIS) barriers by targeting CDK6, SIRT1, and TGFBR2. In the prognostic scenario (ulceration), we identified a specific "stress-adaptive" signature of 23 miRNAs. Notably, the upregulation of hsa-miR-223-3p emerged as a key driver of invasiveness by suppressing the motility-limiting tumor suppressor RHOB, while the concurrent loss of hsa-miR-200c and hsa-miR-489-3p may unleash Epithelial-Mesenchymal Transition (EMT) and EGFR-driven survival pathways. Our study supports a double-switch mechanism where specific miRNA alterations first drive senescence escape and subsequently promote survival in the hypoxic ulcerated niche. These signatures offer robust biomarkers for diagnosis and highlight the miR-142-5p/CDK6 and miR-223-3p/RHOB axes as potential therapeutic targets for precise intervention.

cancer biology↗

bioRxiv2023

An integrated approach to identify sex-specific genes, transcription factors, and pathways in Alzheimer's disease

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/556293v3_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@4a60d7org.highwire.dtl.DTLVardef@11bd7eborg.highwire.dtl.DTLVardef@fc9b69org.highwire.dtl.DTLVardef@3f239f_HPS_FORMAT_FIGEXP M_FIG C_FIG BackgroundAge represents a significant risk factor for the development of Alzheimers disease (AD); however, recent research has documented an influencing role of sex in several features of AD. Understanding the impact of sex on specific molecular mechanisms associated with AD remains a critical challenge to creating tailored therapeutic interventions. MethodsThe exploration of the sex-based differential impact on disease (SDID) in AD used a systematic review to first select transcriptomic studies of AD with data regarding sex in the period covering 2002 to 2021 with a focus on the primary brain regions affected by AD - the cortex (CT) and the hippocampus (HP). A differential expression analysis for each study and two tissue-specific meta-analyses were then performed. Focusing on the CT due to the presence of significant SDID-related alterations, a comprehensive functional characterization was conducted: protein-protein network interaction and over-representation analyses to explore biological processes and pathways and a VIPER analysis to estimate transcription factor activity. ResultsWe selected 8 CT and 5 HP studies from the Gene Expression Omnibus (GEO) repository for tissue-specific meta-analyses. We detected 389 significantly altered genes in the SDID comparison in the CT. Generally, female AD patients displayed more affected genes than males; we grouped said genes into six subsets according to their expression profile in female and male AD patients. Only subset I (repressed genes in female AD patients) displayed significant results during functional profiling. Female AD patients demonstrated more significant impairments in biological processes related to the regulation and organization of synapsis and pathways linked to neurotransmitters (glutamate and GABA) and protein folding, A{beta} aggregation, and accumulation compared to male AD patients. These findings could partly explain why we observe more pronounced cognitive decline in female AD patients. Finally, we detected 23 transcription factors with different activation patterns according to sex, with some associated with AD for the first time. All results generated during this study are readily available through an open web resource Metafun-AD (https://bioinfo.cipf.es/metafun-ad/). ConclusionOur meta-analyses indicate the existence of differences in AD-related mechanisms in female and male patients. These sex-based differences will represent the basis for new hypotheses and could significantly impact precision medicine and improve diagnosis and clinical outcomes in AD patients. HighlightsO_LIFemale AD patients possess more affected genes than male AD patients. C_LIO_LI389 genes from the sex-based differential impact on disease comparison significantly impact the cerebral cortex and suggest a more significant effect on cognitive function in female AD patients. C_LIO_LIThe cluster of repressed genes in female AD patients functionally impacts glutamate and GABA neurotransmitters and A{beta} deposition. C_LIO_LIFemale AD patients exhibit several transcription factors with significantly different activity patterns compared to male AD patients. C_LIO_LIThis work includes Metafun-AD, an open and interactive web tool to explore all generated data and results. C_LI

neuroscience↗