TY - JOUR
T1 - Factor XIIIA-expressing inflammatory monocytes promote lung squamous cancer through fibrin cross-linking
AU - Porrello, Alessandro
AU - Leslie, Patrick L.
AU - Harrison, Emily B.
AU - Gorentla, Balachandra K.
AU - Kattula, Sravya
AU - Ghosh, Subrata K.
AU - Azam, Salma H.
AU - Holtzhausen, Alisha
AU - Chao, Yvonne L.
AU - Hayward, Michele C.
AU - Waugh, Trent A.
AU - Bae, Sanggyu
AU - Godfrey, Virginia
AU - Randell, Scott H.
AU - Oderup, Cecilia
AU - Makowski, Liza
AU - Weiss, Jared
AU - Wilkerson, Matthew D.
AU - Hayes, D. Neil
AU - Earp, H. Shelton
AU - Baldwin, Albert S.
AU - Wolberg, Alisa S.
AU - Pecot, Chad V.
N1 - Funding Information:
The authors would like to especially thank Drs. Stephanie Cohen, Nana Feinberg and Mervi Eeva from the UNC Translational Pathology Lab for their help with immunohistochemistry and processing of the tissue microarrays, the UNC Animal Histopathology Core, and Janet Dow from the UNC Flow Cytometry Core Facility. The authors thank Dr. Antonio Amelio for providing the Fluorescent-Nanoluciferase plasmids. The UNC Translational Pathology Laboratory is supported in part by grants from the NCI (2-P30-CA016086-40), NIEHS (2-P30ES010126-15A1), UCRF, and NCBT (2015-IDG-1007). C.V.P. was supported in part by the National Institutes of Health R01CA215075, a Mentored Research Scholar Grants in Applied and Clinical Research (MRSG-14-222-01-RMC) from the American Cancer Society, the Jimmy V Foundation Scholar award, the UCRF Innovator Award, the Stuart Scott V Foundation/ Lung Cancer Initiative Award for Clinical Research, the University Cancer Research Fund, the Lung Cancer Research Foundation, the Free to Breathe Metastasis Research Award and the Susan G. Komen Career Catalyst Award. S.H.A. was supported in part by a grant from the National Institute of General Medical Sciences under award 5T32 GM007092. E.B.H. was supported in part by a grant from the National Cancer Institute of the National Institutes of Health under award number T32CA196589. S.H.R. was supported in part by NIH P30DK065988. L.M. was supported in part by the University Cancer Research Fund and NCI CA180134. A.B. was supported by NIH R35CA197684. A.S.W. was supported in part by NIH R01HL126974. S.K. was supported in part by NIH F31HL139100. The UNC Flow Cytometry Core Facility and Lineberger Comprehensive Cancer Center Animal Histopathology and Animal Studies Cores are all supported in part by an NCI Center Core Support Grant (CA016086) to the UNC Lineberger Comprehensive Cancer Center. The UNC Flow Cytometry Core Facility is also supported in part by the North Carolina Biotech Center Institutional Support Grant 2012-IDG-1006.The views expressed in this article are those of the authors and do not reflect the official policy of the Department of Defense or U.S. Government.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85047227288&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-04355-w
DO - 10.1038/s41467-018-04355-w
M3 - Article
C2 - 29777108
AN - SCOPUS:85047227288
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1988
ER -