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

Alessandro Porrello, Patrick L. Leslie, Emily B. Harrison, Balachandra K. Gorentla, Sravya Kattula, Subrata K. Ghosh, Salma H. Azam, Alisha Holtzhausen, Yvonne L. Chao, Michele C. Hayward, Trent A. Waugh, Sanggyu Bae, Virginia Godfrey, Scott H. Randell, Cecilia Oderup, Liza Makowski, Jared Weiss, Matthew D. Wilkerson, D. Neil Hayes, H. Shelton Earp, Albert S. Baldwin, Alisa S. Wolberg and Chad V. Pecot ()
Additional contact information
Alessandro Porrello: University of North Carolina at Chapel Hill
Patrick L. Leslie: University of North Carolina at Chapel Hill
Emily B. Harrison: University of North Carolina at Chapel Hill
Balachandra K. Gorentla: University of North Carolina at Chapel Hill
Sravya Kattula: University of North Carolina at Chapel Hill
Subrata K. Ghosh: University of North Carolina at Chapel Hill
Salma H. Azam: University of North Carolina at Chapel Hill
Alisha Holtzhausen: University of North Carolina at Chapel Hill
Yvonne L. Chao: University of North Carolina at Chapel Hill
Michele C. Hayward: University of North Carolina at Chapel Hill
Trent A. Waugh: University of North Carolina at Chapel Hill
Sanggyu Bae: University of North Carolina at Chapel Hill
Virginia Godfrey: University of North Carolina at Chapel Hill
Scott H. Randell: University of North Carolina at Chapel Hill
Cecilia Oderup: Cancer Immunology, Pfizer, Inc
Liza Makowski: University of North Carolina at Chapel Hill
Jared Weiss: University of North Carolina at Chapel Hill
Matthew D. Wilkerson: Physiology and Genetics, The American Genome Center, Collaborative Health Initiative Research Program, Uniformed Services University
D. Neil Hayes: University of North Carolina at Chapel Hill
H. Shelton Earp: University of North Carolina at Chapel Hill
Albert S. Baldwin: University of North Carolina at Chapel Hill
Alisa S. Wolberg: University of North Carolina at Chapel Hill
Chad V. Pecot: University of North Carolina at Chapel Hill

Nature Communications, 2018, vol. 9, issue 1, 1-19

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04355-w

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