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

A Porrello, PL Leslie, EB Harrison, BK Gorentla… - Nature …, 2018 - nature.com
A Porrello, PL Leslie, EB Harrison, BK Gorentla, S Kattula, SK Ghosh, SH Azam…
Nature communications, 2018nature.com
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 …
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.
nature.com