Single-Cell RNA Sequencing Identifies MMP11⁺ Cancer-Associated Fibroblasts as Drivers of Angiogenesis and Bladder...

Area of Science:

• Oncology
• Cancer Biology
• Immunology

Background:

• Cancer-associated fibroblasts (CAFs) exhibit heterogeneity, impacting tumor progression, therapeutic response, and patient prognosis.
• Understanding CAF heterogeneity is crucial for developing effective cancer treatments.

Purpose of the Study:

• To identify and characterize novel CAF subgroups involved in bladder cancer progression.
• To elucidate the mechanisms by which specific CAFs regulate tumor growth and angiogenesis.
• To explore the therapeutic potential of targeting identified CAF populations across various cancer types.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) to identify CAF heterogeneity.
• Analysis of signaling pathways (WNT5A-MCAM, CCL11/CCL2) involved in CAF-mediated tumor regulation.
• In vivo mouse models to assess the efficacy of targeting BMP2 signaling.
• Pan-cancer analysis to determine the prevalence of identified CAF subgroups.

Main Results:

• A novel CAF subgroup, MMP11+ myeloid-derived CAFs (mCAFs), was identified, accumulating during bladder cancer progression and linked to poor prognosis.
• MMP11+ mCAFs regulate endothelial cell migration via WNT5A-MCAM signaling and modulate SOX18, NFIC, and HOXB9 expression.
• MMP11+ mCAFs recruit macrophages, promoting VEGFA-driven angiogenesis, and are influenced by tumor cell-secreted BMP2.
• Inhibition of BMP2 suppressed tumor angiogenesis and growth in mouse models.
• MMP11+ mCAFs are prevalent in multiple cancer types, including breast, lung, gastric, and colorectal cancers.

Conclusions:

• MMP11+ mCAFs represent a distinct CAF subtype driving bladder cancer progression and angiogenesis.
• The BMP2-NFE2L3-WNT5A axis is a key regulatory pathway involving MMP11+ mCAFs.
• Targeting MMP11+ mCAFs or related pathways presents a potential pan-cancer therapeutic strategy.