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

Nature Communications
Alessandro PorrelloChad V Pecot

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.

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Citations

Nov 1, 2018·Journal of Cellular Physiology·Masoud NajafiKeywan Mortezaee
Feb 19, 2019·Journal of Leukocyte Biology·Claire E OlingyCatherine C Hedrick
Sep 17, 2019·Chemical Communications : Chem Comm·Masayasu KuwaharaNaoki Sugimoto
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Aug 7, 2021·Communications Biology·Sandra Gómez-LópezSam M Janes

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Datasets Mentioned

BETA
GSE112585

Methods Mentioned

BETA
RNA-seq
immunogenomic
ELISA
flow cytometry
FACS
surgical resection
Assay
Blood Collection
fluorescence microscopy
scraping

Software Mentioned

Gene Set Enrichment Analysis ( GSEA )
GSEA
Gene Set Enrichment Analyses ( GSEA )
IPA
Ingenuity Pathway Analysis ( IPA )
Cytoscape
Affymetrix GeneChip Command Console ( AGCC )
RSEM
Tissue
Tissue Studio Composer

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