Biology subjects

Gomez-Munoz, M. A.

Publications and source records attributed to Gomez-Munoz, M. A..

3 recordsLinked to original sources

bioRxiv2026

Cross-species spatial profiling links progranulin to an immune suppressive niche in brain metastasis

Immune checkpoint inhibitors (ICI) have revolutionized the treatment of brain metastasis (BM), demonstrating intracranial response rates and durability not previously seen with other therapies. However, approximately 50% of patients do not respond to ICI, and the brain-specific interactions that shape anti-tumor immunity remain poorly understood. We profiled five syngeneic BM models using spatial transcriptomics, identifying myeloid-rich niches enriched for interferon-responsive and disease-associated microglia (DAM)-like programs. Ligand-receptor colocalization analyses identified progranulin (PGRN) as a candidate mediator of these niches. Host- or tumor-cell Grn loss reduced BM burden, and Grn-deficient macrophages exhibited altered metabolic programs and tumor-cell engulfment in vitro. Across independent human BM datasets, GRN expression was associated with conserved lysosomal and DAM-like myeloid programs, and GRN-high myeloid regions colocalized with immunosuppressive signatures and dysfunctional CD8+ T cell states. These cross-species findings identify PGRN as a candidate mediator of the BM immune niche and support further investigation of its therapeutic relevance.

cancer biology↗

bioRxiv2025

The carnosinase dipeptidase CNDP1 is a novel metabolic vulnerability in brain metastasis

Brain metastatic cells undergo metabolic adaptations, such as increased reliance on oxidative phosphorylation. Integrating proteomic and transcriptomic profiling of patient samples revealed a consistent upregulation of the carnosine dipeptidase-1 (CNDP1) in brain versus extracranial metastases. Carnosine is an abundant metabolite in brain and muscle, known to exert anti-proliferative effects on cancer cells. Here, we demonstrate that CNDP1 inhibition suppresses both the establishment and maintenance of melanoma brain metastasis while its ectopic expression is sufficient to confer brain metastatic potential to poorly metastatic cells. CNDP1 suppression results in activation of the Integrated Stress Response via Heme-Regulated Inhibitor Kinase and reprogrammed translation towards preferential expression of mitochondrial and survival transcripts. We further show that CNDP1 upregulation supports mitochondrial activity by limiting the levels of its substrate carnosine, a copper ionophore, thus protecting metastatic cells from carnosine-induced copper toxicity. Our studies reveal a novel metabolic adaptation during brain metastasis, which can be leveraged for therapeutic purposes.

cancer biology↗

bioRxiv2024

Rho GTPases signaling mediates aggressiveness and differentiation in neuroblastoma tumors

BackgroundNeuroblastoma (NB) is a pediatric cancer with highly variable outcomes, necessitating improved understanding of the molecular pathways driving its progression. Intratumor cellular heterogeneity related to neural differentiation has emerged as a defining characteristic that can explain its aggressive behavior. Although recurrent driver mutations are not typically observed in these tumors, Rho GTPases signaling genes have been identified as one of the most frequently mutated in aggressive NB cases. Rho GTPases are key regulators of cell morphology, migration, and differentiation, yet their role in NB remains underexplored. This study aims to comprehensively evaluate the expression and clinical significance of Rho GTPase signaling networks in NB tumors. MethodsWe analyzed the expression profiles of Rho GTPases, their regulators, and effectors, across multiple NB patient cohorts. Gene expression correlations with clinical parameters were assessed, and bioinformatics analyses were employed to identify gene expression patterns and interactions in tumors. Functional studies were performed in NB cell lines and in vivo models to validate the role of key Rho GTPases, including Cdc42, in NB progression and differentiation. ResultsOur analysis revealed widespread dysregulation of Rho GTPase signaling in NB tumors. Specific GTPases, such as RHOA or RHOV, were upregulated in advanced disease stages, while others, including RHOB, RHOU and CDC42, were downregulated and associated with poor prognosis. A minimal Rho-related gene signature was identified as a strong predictor of NB patient survival. Functional validation highlighted Cdc42 as a key regulator of NB differentiation, where its downregulation was necessary for maintaining the malignant, undifferentiated phenotype of NB cells. We also identified ARHGAP31/CdGAP as a critical regulator of Cdc42 in NB progenitor cells, suggesting a mechanism for Cdc42 suppression in aggressive NB. ConclusionsAn important role for Rho GTPase signaling in NB progression is revealed, providing a foundation for further exploration of Rho GTPase-targeted therapies in NB. In particular, Cdc42 signaling intervene in the balance between differentiation and stemness in NB cells, suggesting specific signaling events controlling the identity and plasticity of NB cells.

cancer biology↗