Biology subjects

Olmeda, D.

Publications and source records attributed to Olmeda, D..

4 recordsLinked to original sources

bioRxiv2026

lisaR: An LLM-Inferred Semantic Annotation of biological categories for gene set enrichment analysis

Gene set enrichment analysis (GSEA) turns differential expression results into lists of enriched gene sets. These lists are often long and redundant and span several gene-set collections, which makes their biological interpretation difficult. We present lisaR, an R package that reads previously computed differential expression or differential abundance results, runs GSEA and organises the output with the LISA dictionaries (LLM-Inferred Semantic Annotation). The dictionaries place 13,511 gene sets from the three Gene Ontology branches and from curated pathway collections such as Reactome, WikiPathways, KEGG, BioCarta and PID in 158 biological categories grouped into 42 supercategories within four dictionaries. Four open-weight language models scored the semantic fit of each gene set to the categories, and a consensus rule selected the assignments. The dictionaries are distributed with the package and do not depend on the data: studies analysed at different times with the same dictionaries are interpreted with the same categories, and no language model is queried during an analysis. For each category, lisaR summarises the direction of its significant gene sets and applies closed testing with Hommel's robust procedure, which states whether the category shows evidence of enrichment and gives a simultaneous lower bound on how many of its gene sets are enriched. lisaR results are summarised in a report that opens in a web browser and leads from each category to its gene sets and genes, with every figure saved together with its data and R code. We illustrate the workflow with RNA-seq from melanoma biopsies taken before and during nivolumab treatment and with paired tumour and adjacent-tissue proteomics from clear cell renal cell carcinoma. Availability: lisaR is available at https://github.com/DBM-OlmedaLab/lisaR and archived at https://doi.org/10.5281/zenodo.23044930; documentation at https://olmedalab.org/lisaR/.

bioinformatics↗

bioRxiv2025

Midkine inhibits dormancy of disseminated melanoma cells

A major challenge in melanoma treatment is the emergence of aggressive metastases from previously dormant disseminated cancer cells (DCCs). Here we identify Midkine (MDK) as a key factor that disrupts melanoma DCC dormancy by triggering an autocrine signal that suppresses the dormancy inducer NR2F1 and alters the p-p38/p-ERK ratio, via ALK signaling. Dormant melanoma DCCs in lymph nodes and visceral tissues exhibit an MDKLOW/NR2F1HIGH phenotype. Transient NR2F1 activation for one month with a potent agonist counteracts MDK-driven mTORC1 activity and suppresses lung metastasis in mice bearing human melanoma DCCs. Dual targeting of MDK (genetic blockade) and NR2F1 (activation) markedly limits metastatic outgrowth and extends survival for 6 months in mouse models independent of BRAF status. These findings support the MDK-NR2F1 axis as a promising therapeutic target to sustain dormancy and prevent melanoma recurrence. Statement of SignificanceThis work identifies Midkine as a key disruptor of tumor dormancy in melanoma, driving metastatic awakening via NR2F1 suppression. Dual targeting of Midkine (inhibition) and NR2F1 (activation) prolongs survival in preclinical models.

cancer biology↗

bioRxiv2022

Systemic effects of melanoma-secreted MIDKINE in the inhibition of dendritic cell differentiation and function

Cutaneous melanomas are a prime example of potentially immunogenic tumors, and as such, ideal targets for immune therapy. These lesions have the largest mutational burden described to date, and accumulate a broad spectrum of post-transcriptional and translational alterations that could conceptually result in a plethora of neoantigens for immune recognition. However, a significant fraction of metastatic melanoma patients is or becomes resistant to current immunotherapeutic agents. How lesions that should represent an inherently hot milieu for immune attack shift into immunologically cold or irresponsive neoplasms is not well understood. Combining cellular systems, mouse models and clinical datasets, here we identify the growth factor Midkine (MDK) as a multipronged blocker of antigen presentation. Mechanistically, we found MDK to repress all main aspects of the maturation, activation and function of dendritic cells, particularly of conventional type 1 (cDC1). These roles of MDK were found to involve primary tumors and lymph nodes, and were traced back to suppressive effects on myeloid precursor cells in the bone marrow. Moreover, MDK shifted the transcriptional profile of DCs towards a tolerogenic state that prevented and bypassed CD8+ T cell activation. Blocking MDK enhanced the response to DC-based vaccination and improved the response to immune checkpoint blockade.Together, these data provide insight into how melanomas overcome immune surveillance and support MDK as a target for therapeutic intervention.

cancer biology↗

bioRxiv2019

Antimetastatic dsRNA mimics identified by live imaging of pathogenic neolymphangiogenesis

The crosstalk between cancer cells and the lymphatic vasculature has long been proposed to define competency for metastasis. Nevertheless, the discovery of selective blockers of lymphovascular niches has been compromised by the paucity of experimental systems for whole-body analyses of tumor progression. Here we present immunocompetent and immunodeficient mouse models for live imaging of melanoma-induced neolymphangiogenesis (driven by Vegfr3) as a cost-effective platform for drug screening in vivo. Spatio-temporal analyses in autochthonous melanomas and patient-derived xenografts identified double stranded RNA mimics (dsRNA nanoplexes) as potent repressors of lymphangiogenesis and metastasis. Mechanistically, dsRNA nanoplexes were found to suppress lymphangiogenic drivers in both tumor cells and their associated lymphatic vasculature (via MIDKINE and Vegfr3, respectively). This dual inhibitory action, driven by type I interferon, was not shared by FDA-approved antimelanoma treatments or by lymphangiogenic blockers in clinical testing. These results underscore the power of Vegfr3-lymphoreporters for pharmacological testing in otherwise aggressive cancers. RELEVANCEAlthough tumor-induced lymphangiogenesis has long been associated with metastasis, selective targeting of this process has been compromised by the paucity of experimental platforms for whole-body imaging of tumor progression and drug response. Here we present animal models engineered for spatio-temporal analyses of neolymphangiogenesis in clinically relevant autochthonous melanomas and patient-derived xenografts, and identify a unique action of double stranded-RNA nanoplexes as potent repressors of lymphatic dissemination and metastatic relapse.

cancer biology↗