Factor XIIIA\u2014expressing inflammatory monocytes promote lung squamous cancer through fibrin cross-linking

Alessandro Porrello,Emily B Harrison,D Neil Hayes,Alisa S Wolberg,Yvonne Chao ,Sanggyu Bae,Subrata Ghosh ,Matthew D Wilkerson,Alisha Holtzhausen,Scott H Randell,Balachandra K Gorentla,Jared Weiss,Cecilia Oderup,Salma H Azam,Liza Makowski,Albert S Baldwin,H Shelton Earp,Sravya Kattula,Virginia Godfrey,Michele C Hayward,Trent A Waugh,Patrick L Leslie,Chad V Pecot

doi:10.1038/s41467-018-04355-w

Alessandro Porrello, Emily B Harrison + Show 21 more

Open Access

https://doi.org/10.1038/s41467-018-04355-w

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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.

Highlights

Lung cancer is the leading cause of cancer-related deaths worldwide, and lung squamous carcinomas (LUSC) represent about 30% of cases
Our results have identified a previously unappreciated driver of LUSC metastasis characterized by CCL2-mediated recruitment of inflammatory monocytes (IMs) and factor XIII-A subunit (FXIIIA)-mediated fibrin cross-linking in the tumor microenvironment (TME), which provides a scaffold for tumor cell invasion
Given the robust immunologic response that LN4K1 invokes in the lung TME, we addressed whether the CCL2-mediated recruitment of IMs is necessary and sufficient for distant metastasis development in LUSC using an experimental metastasis model

Summary

Introduction

Lung cancer is the leading cause of cancer-related deaths worldwide, and lung squamous carcinomas (LUSC) represent about 30% of cases. The Secretory subtype was defined by an immuneresponse signature rich in genes associated with complement activation, immune cell recruitment, and inflammation8 Building upon these observations, we computationally analyzed the LUSC TCGA dataset and identified a new and previously unappreciated subset of LUSC patients that is highly associated with inflammatory monocyte (IM) infiltration and very poor survival. Our results have identified a previously unappreciated driver of LUSC metastasis characterized by CCL2-mediated recruitment of IMs and FXIIIA-mediated fibrin cross-linking in the TME, which provides a scaffold for tumor cell invasion. This novel mechanism is reflected in clinical samples where fibrin cross-linking is correlated with poor survival. IMs in LUSC tumors represent an important contextspecific vulnerability of this difficult-to-treat disease

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