LRG1 Drives Pathological Angiogenesis by Disrupting Neutrophil Mitochondrial Homeostasis in Bladder Cancer

Area of Science:

• Oncology
• Immunology
• Vascular Biology

Background:

• Abnormal tumor vasculature in bladder cancer (BCa) promotes malignant progression.
• Leucine-rich alpha-2 glycoprotein 1 (LRG1) is implicated in angiogenesis, but its role in BCa microenvironment remodeling is unclear.

Purpose of the Study:

• To elucidate the specific role of LRG1 in regulating the BCa microenvironment and vascular integrity.
• To investigate the molecular mechanisms by which LRG1 influences tumor progression and therapeutic response.

Main Methods:

• Integrated single-cell RNA sequencing (scRNA-seq) and bulk transcriptomics.
• Utilized BCa mouse models, neutrophil depletion, DNase I treatment, and clinical specimens for functional validation.
• Performed molecular interactome mapping using pull-down assays, mass spectrometry, and confocal imaging.

Main Results:

• LRG1 is upregulated in BCa, correlating with metastasis and poor prognosis.
• Tumor-derived LRG1 binds to Annexin A2 on neutrophils, triggering mtROS-dependent Neutrophil Extracellular Traps (NETs) release.
• NETs destabilize tumor vasculature by reducing mural cell coverage, while LRG1 blockade normalizes vessels.

Conclusions:

• The LRG1-neutrophil-NETosis axis critically drives vascular dysfunction and therapeutic resistance in BCa.
• Targeting this axis represents a promising strategy to improve drug delivery, T-cell infiltration, and sensitize BCa to chemotherapy and immunotherapy.
• Vascular normalization via LRG1 blockade offers a translational approach to enhance BCa treatment outcomes.