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

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. H...

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Detalles Bibliográficos
Autores principales: Porrello, Alessandro, Leslie, Patrick L., Harrison, Emily B., Gorentla, Balachandra K., Kattula, Sravya, Ghosh, Subrata K., Azam, Salma H., Holtzhausen, Alisha, Chao, Yvonne L., Hayward, Michele C., Waugh, Trent A., Bae, Sanggyu, Godfrey, Virginia, Randell, Scott H., Oderup, Cecilia, Makowski, Liza, Weiss, Jared, Wilkerson, Matthew D., Hayes, D. Neil, Earp, H. Shelton, Baldwin, Albert S., Wolberg, Alisa S., Pecot, Chad V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959879/
https://www.ncbi.nlm.nih.gov/pubmed/29777108
http://dx.doi.org/10.1038/s41467-018-04355-w
Descripción
Sumario: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.