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Implantation of Fibrin Gel on Mouse Lung to Study Lung-specific Angiogenesis
Published on: December 21, 2014
Factor XIIIA-expressing inflammatory monocytes promote lung squamous cancer through fibrin cross-linking
Alessandro Porrello1, Patrick L Leslie1, Emily B Harrison2
1UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Abstract:
Lung cancer is the leading cause of cancer-related deaths worldwide, and lung squamous carcinomas (LUSC) represent about 30% of cases. Molecular aberrations in lung adenocarcinomas have allowed for effective targeted treatments, but corresponding therapeutic advances in LUSC have not materialized. However, immune checkpoint inhibitors in sub-populations of LUSC patients have led to exciting responses. Using computational analyses of The Cancer Genome Atlas, we identified a subset of LUSC tumors characterized by dense infiltration of inflammatory monocytes (IMs) and poor survival. With novel, immunocompetent metastasis models, we demonstrated that tumor cell derived CCL2-mediated recruitment of IMs is necessary and sufficient for LUSC metastasis. Pharmacologic inhibition of IM recruitment had substantial anti-metastatic effects. Notably, we show that IMs highly express Factor XIIIA, which promotes fibrin cross-linking to create a scaffold for LUSC cell invasion and metastases. Consistently, human LUSC samples containing extensive cross-linked fibrin in the microenvironment correlated with poor survival.
Insights
Inflammatory monocytes (IMs) drive lung squamous carcinoma (LUSC) metastasis by creating a fibrin scaffold. Targeting IM recruitment offers a promising anti-metastatic strategy for LUSC patients.
Area of Science:
- Oncology
- Immunology
- Cancer Metastasis
Background:
- Lung squamous cell carcinoma (LUSC) lacks targeted therapies, unlike lung adenocarcinoma.
- Immune checkpoint inhibitors show promise in a subset of LUSC patients.
- Identifying novel therapeutic targets in LUSC is critical.
Purpose of the Study:
- To investigate the role of tumor microenvironment in LUSC metastasis.
- To identify molecular mechanisms driving LUSC progression.
- To explore potential therapeutic strategies targeting metastasis.
Main Methods:
- Computational analysis of The Cancer Genome Atlas (TCGA) data.
- Development and utilization of immunocompetent metastasis models.
- Pharmacologic inhibition of inflammatory monocyte recruitment.
- Assessment of Factor XIIIA expression and fibrin cross-linking.
Main Results:
- A subset of LUSC tumors with high inflammatory monocyte (IM) infiltration correlates with poor survival.
- CCL2-mediated IM recruitment is essential and sufficient for LUSC metastasis.
- Inhibiting IM recruitment demonstrated significant anti-metastatic effects.
- IMs express Factor XIIIA, promoting a fibrin scaffold for LUSC invasion.
- Fibrin cross-linking in human LUSC samples is linked to poor survival.
Conclusions:
- Tumor-recruited inflammatory monocytes are key drivers of LUSC metastasis.
- Targeting the CCL2-mediated monocyte recruitment pathway offers a novel therapeutic approach.
- Factor XIIIA-mediated fibrin cross-linking by monocytes contributes to LUSC progression.
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