LGMN+ Macrophages Promote Tumor Supportive Microenvironment in Gastric Cancer

14 Apr 20264 min read0 viewsJournal Feed

GIST

BackgroundTumor-associated macrophages (TAMs) are known to facilitate cancer progression. However, the diversity of TAM subsets and their distinct roles in GC remain poorly understood.

This study aimed to evaluate the impact of legumain (LGMN)+ macrophages on GC progression and clarify the underlying mechanisms of their roles.MethodsWe used single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (bulk RNA-seq) analyses from public databases (GEO and TCGA) to systematically evaluate the clinical prognostic significance of LGMN and to characterize the remodeling of its associated signaling pathways. To investigate the role of LGMN in mouse GC (TAMs), we generated macrophage-specific LGMN conditional knockout mice, LGMNflox/flox; Lyz2-Cre.

Utilizing a combination of subcutaneous xenograft tumor models, primary cell isolation and culture, immunofluorescence staining, and tube formation assays, we systematically elucidated the regulatory function and underlying molecular mechanisms of LGMN+ macrophages in GC progression.ResultsWe found that LGMN+ macrophages are significantly enriched in GC tissues, and their high infiltration was significantly associated with poor outcomes. Additionally, scRNA-seq revealed that hypoxia and immune suppression pathways are enriched in LGMN+ macrophages.

Clinical Editorial

Summary

LGMN+ Macrophages in Gastric Cancer: A Targetable Driver of a Pro-Tumor Microenvironment:

Context and aims

The study addresses tumor-associated macrophage (TAM) heterogeneity in gastric cancer (GC) and investigates the impact of legumain-positive (LGMN+) macrophages on GC progression.
The authors seek to clarify the signaling pathways associated with LGMN+ macrophages and their mechanistic role in tumor biology.

Study design and analytical approach

The investigation integrates single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (bulk RNA-seq) from public repositories (GEO and TCGA) to assess prognostic relevance of LGMN and characterize remodeling of related pathways.
In murine models, macrophage-specific LGMN conditional knockout mice (LGMNflox/flox; Lyz2-Cre) were employed to probe functional consequences in gastric cancer.
Experimental paradigms included subcutaneous xenografts, primary cell isolation and culture, immunofluorescence, and tube formation assays to delineate mechanism and effect sizes.

Key findings and cellular context

LGMN+ macrophages are enriched in GC tissues, with higher infiltration correlating with poorer clinical outcomes.
scRNA-seq indicates enrichment of hypoxia and immunosuppressive pathways within LGMN+ macrophage populations.
A notable positive association exists between LGMN+ macrophage presence and infiltration by regulatory T (Treg) cells and endothelial cells, suggesting a microenvironment shaped by both immunosuppression and angiogenesis.

Functional impact of LGMN deletion in macrophages

Macrophage-restricted LGMN knockout reorients TAMs toward an anti-tumor phenotype, accompanied by reduced Treg cell infiltration and increased CD8+ T cell presence within the tumor milieu.
LGMN deficiency diminishes tumor angiogenesis, aligning with lowered VEGF-A expression.

Implications and limitations

The data support a model in which LGMN+ macrophages drive GC progression by promoting angiogenesis and an immunosuppressive microenvironment.
Targeting LGMN+ macrophages emerges as a potential therapeutic strategy in GC.
Limitations include reliance on murine models and retrospective sequencing analyses; prospective validation and functional dissection in diverse GC contexts are needed to establish translational relevance.