Biology subjects

Lopez-Navarro, B.

Publications and source records attributed to Lopez-Navarro, B..

3 recordsLinked to original sources

bioRxiv2026

G-CSF associates with poor survival in cutaneous melanoma and promotes metastasis through coordinated effects on macrophages and tumor cells

Macrophage-melanoma interactions critically shape the tumor microenvironment, yet the cytokine networks driving this process remain incompletely understood. Among these, colony-stimulating factors--particularly granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF or CSF3)--regulate myeloid cell behavior during cancer progression, although their specific roles in melanoma remain unclear. Using co-culture systems of melanoma and monocyte-derived macrophages, we found that GM-CSF-primed macrophages induced robust G-CSF secretion and concurrent CSF3 upregulation in both cell compartments. Moreover, transcriptomic profiling of patient-derived tumor-associated macrophages (TAMs) confirmed elevated CSF3 and CSF3R expression in metastatic melanoma. Multiplex immunofluorescence analysis of a stage II-IV primary melanoma cohort (n=84) revealed increased G-CSF and CD114 expression in TAMs and tumor cells from patients who subsequently developed metastasis. High G-CSF levels in either TAMs or melanoma cells emerged as an independent prognostic factor for shorter disease-free and overall survival (p < 0.001). Mechanistically, G-CSF activated STAT1/STAT3 signaling in melanoma cells and promoted proliferation and invasion in a CD114-dependent manner. Of note, G-CSF drove monocyte differentiation toward a distinct inflammatory macrophage state characterized by STAT1/STAT3 activation and a pro-invasive secretory profile. Furthermore, melanoma cells conditioned by G-CSF-differentiated macrophages displayed increased in vivo lung colonization and enriched transcriptional programs linked to invasion and proliferation. Collectively, these findings establish the G-CSF/CD114 axis as a potential clinically relevant driver of melanoma metastasis and identify G-CSF as a novel independent prognostic biomarker. HIGHLIGHTSO_LIDespite its extended clinical use, G-CSF role in human melanoma remains undefined. C_LIO_LIHigh G-CSF expression in primary melanomas correlates with poor patient survival. C_LIO_LIG-CSF promotes melanoma cell invasion and proliferation through CD114 signaling. C_LIO_LIG-CSF drives macrophage differentiation toward a pro-tumoral phenotype. C_LIO_LIMelanoma cells conditioned by G-CSF-primed macrophages are more metastatic. C_LI

cancer biology↗

bioRxiv2025

Adverse prognosis of GM-CSF expression in human cutaneous melanoma

Tumor-associated macrophages (TAMs) represent a major immune population within the tumor microenvironment, influencing cancer progression and immune responses. Our group previously identified a subset of pro-inflammatory TAMs associated with poor prognosis in human melanoma. GM-CSF, a myeloid-priming cytokine, exhibits context-dependent effects on tumor growth and, despite its clinical use, its role in human melanoma remains undefined. In this study, we demonstrate that GM-CSF is significantly enriched in primary cutaneous melanoma samples from patients who subsequently developed metastasis, compared with non-metastasizing ones. By quantifying GM-CSF expression in TAMs and tumor cells (TCs), we found that high levels, in both TAMs and TCs, correlated with reduced disease-free and overall survival (p< 0.0001). Although GM-CSF receptor subunits were present in TCs and TAMs, their expression did not correlate with clinical outcomes. To explore the pro-metastatic role of GM-CSF, we performed in vitro assays and found that it activates non-canonical signaling pathways, such as STAT3 and PI3K/AKT, and promotes melanoma cell invasion. Consistently, its administration enhanced lung colonization by melanoma cells in a murine model, an effect reversed by CD116 receptor blockade. Furthermore, GM-CSF-primed macrophages secreted higher levels of inflammatory cytokines upon interaction with melanoma cells than those unprimed or primed with the counterpart cytokine M-CSF. Reciprocally, RNA-seq analyses revealed a broader transcriptional reprogramming in melanoma cells exposed to GM-CSF-primed macrophages, which displayed enhanced expression of inflammatory-response genes, suggesting a feedforward loop. Altogether, our findings highlight a potentially pro-tumorigenic GM-CSF-driven paracrine axis in patients with poor-prognosis melanoma, supporting therapeutic strategies aimed at disrupting this signaling network.

cancer biology↗

bioRxiv2024

Re-programming of GM-CSF-dependent alveolar macrophages through GSK3 activity modulation

Monocyte-derived macrophages recruited into inflamed tissues can acquire an array of functional states depending on the extracellular environment. Since the anti-inflammatory/pro-fibrotic macrophage profile is determined by MAFB, whose activity/protein levels are regulated by GSK3, we addressed the macrophage re-programming potential of GSK3 modulation. GM-CSF-dependent (GM-MO) and M-CSF-dependent monocyte-derived macrophages (M-MO) exhibited distinct levels of inactive GSK3, and inhibiting GSK3 in GM-MO led to acquisition of transcriptional, phenotypic and functional properties characteristic of M-MO (enhanced expression of IL-10 and monocyte-recruiting factors, and higher efferocytosis). These re-programming effects were also observed upon GSK3/{beta} knockdown, and through GSK3 inhibition in ex vivo isolated human alveolar macrophages (AMO). Notably, GSK3 downmodulation potentiated the transcriptional signature of Interstitial Macrophages (IMO) while suppressed the AMO-specific gene profile. Indeed, heightened levels of inactive GSK3 and MAFB-dependent proteins were observed in severe COVID-19 patients lung macrophages, highlighting the GSK3-MAFB axis as a therapeutic target for macrophage re-programming.

immunology↗