Biology subjects

Sanchez-Mateos, P.

Publications and source records attributed to Sanchez-Mateos, P..

5 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↗

bioRxiv2025

Translating Genetics into Tissue: Inflammatory Cytokine-Producing TAMs and PD-L1 Tumor Expression as Poor Prognosis Factors in Cutaneous Melanoma

Myeloid cells within tumor microenvironments exhibit significant heterogeneity and play a critical role in influencing clinical outcomes. In this study, we investigated the infiltration of various myeloid cell subtypes in a cohort of cutaneous melanomas, revealing no significant correlation between myeloid cell densities and the occurrence of distant metastasis. We further examined the phenotypic characteristics of primary melanoma tumor-associated macrophages (TAMs) utilizing the seven-phenotype classification recently proposed by Ma et al., derived from extensive pan-cancer single-cell RNA-sequencing studies. First, we analyzed the transcriptomic profile of TAMs isolated from stage IV metastasizing primary melanomas, alongside melanoma-conditioned monocytes cultured in vitro, both supporting the inflammatory cytokine-producing macrophage phenotype. Next, we employed multicolor fluorescence confocal microscopy, to assess the expression of TAM phenotype markers at the protein level in a cohort of primary melanoma samples. Notably, markers indicative of the inflammatory TAM phenotype, quantified at single-cell level, were significantly enriched in metastasizing tumors, demonstrating an independent correlation with shorter disease-free and overall survival (log-rank test, p< 0.0002). Additionally, our screening of phenotype markers expression revealed that PD-L1 positivity in tumor cells, rather than in TAMs, was associated with poor prognosis, highlighting a novel aspect of the immune landscape in cutaneous melanoma.

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↗

bioRxiv2023

Chemokine profiling of melanoma-macrophage crosstalk identifies CCL8 and CCL15 as prognostic factors in cutaneous melanoma

During cancer evolution, tumor cells attract and dynamically interact with monocytes/macrophages. To find biomarkers of disease progression in human melanoma, we used unbiased RNA sequencing and secretome analyses of tumor-macrophage co-cultures. Pathway analysis of genes differentially modulated in human macrophages exposed to melanoma cells revealed a general upregulation of inflammatory hallmark gene sets, particularly chemokines. A selective group of chemokines, including CCL20, CCL15 and CCL8, was actively secreted upon melanoma-macrophage co-culture. Because we previously described the role of CCL20 in melanoma, we focused our study in CCL8 and CCL15, and confirmed that in vitro both chemokines contributed to melanoma survival, proliferation and 3D invasion, through CCR1 signaling. In vivo, both chemokines enhanced primary tumor growth, spontaneous lung metastasis and circulating tumor cell (CTC) survival and lung colonization in mouse xenograft models. Finally, we explored the clinical significance of CCL8 and CCL15 expression in human skin melanoma, screening a collection of 67 primary melanoma samples, by multicolor staining and quantitative image analysis of chemokine-chemokine receptor content at the single cell level. Primary skin melanomas displayed high CCR1 expression, but there was no difference in its level of expression between metastatic and non-metastatic cases. By contrast, the comparative analysis between these two clinically divergent groups showed a highly significant difference in the cancer cell content of CCL8 (P= 0.025) and CCL15 (P< 0.0001). Kaplan-Meier curves showed that high content of CCL8 or CCL15 in cancer cells correlated with shorter disease-free and overall survival (log-rank test, p< 0.001). Our results highlight the role of CCL8 and CCL15, which are highly induced by melanoma-macrophage interactions in biologically aggressive primary melanomas, and could be clinically applicable biomarkers for patient profiling.

cancer biology↗