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

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.

Monocyte heterogeneity and functions in cancer

“…Similar to other components of the tumor microenvironment, the ECM becomes dysregulated during tumorigenesis, altering cell migration, biomechanics, and signaling . Classical monocytes are able to remodel the ECM through expression of factor XIIIA, which promotes cross‐linking of fibrin that accumulates in tumor through leaky vasculature . Densely cross‐linked fibrin provides a scaffold for metastatic tumor cell invasion and is associated with CD14 expression and disease progression in non‐small lung cancer patients .…”

“…Classical monocytes are able to remodel the ECM through expression of factor XIIIA, which promotes cross‐linking of fibrin that accumulates in tumor through leaky vasculature . Densely cross‐linked fibrin provides a scaffold for metastatic tumor cell invasion and is associated with CD14 expression and disease progression in non‐small lung cancer patients . Mϕs derived from CCR2 + monocytes can directly degrade the ECM within tumors by endocytosing deposited collagen .…”

“…102 Densely cross-linked fibrin provides a scaffold for metastatic tumor cell invasion and is associated with CD14 expression and disease progression in non-small lung cancer patients. 102…”

Potentials of C‐C motif chemokine 2–C‐C chemokine receptor type 2 blockers including propagermanium as anticancer agents

“…In addition, PF‐04136309 treatment significantly attenuated lung metastasis of lung squamous carcinomas cells injected i.v. in mice . Giving CCX872‐B, another small‐molecule antagonist of CCR2, prolonged overall survival in a mouse model of breast cancer, although it neither extended tumor‐free survival nor suppressed tumor growth …”

“…in mice. 41 Giving CCX872-B, another small-molecule antagonist of CCR2, prolonged overall survival in a mouse model of breast cancer, although it neither extended tumorfree survival nor suppressed tumor growth. 42 On the basis of the preclinical findings for the potential of PF-04136309 for treatment of pancreatic cancer, a phase 1 clinical trial (NCT01413022) was conducted for this agent in combination with FOLFIRINOX in patients with nonmetastatic PDAC.…”