Factor XIIIA-expressing inflammatory monocytes promote lung squamous cancer through fibrin cross-linking

Nat Commun. 2018 May 18;9(1):1988. doi: 10.1038/s41467-018-04355-w.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor / chemistry
  • Biomarkers, Tumor / immunology
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / immunology*
  • Carcinoma, Squamous Cell / pathology
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / immunology
  • Factor XIIIa / genetics
  • Factor XIIIa / immunology*
  • Female
  • Fibrin / chemistry*
  • Fibrin / immunology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology*
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred DBA
  • Monocytes / immunology*
  • Neoplasm Invasiveness

Substances

  • Biomarkers, Tumor
  • CCL2 protein, human
  • Chemokine CCL2
  • Fibrin
  • Factor XIIIa