Pancreatic Cancer Cell Migration and Metastasis Is Regulated by Chemokine-Biased Agonism and Bioenergetic Signaling.
Patients with pancreatic ductal adenocarcinoma (PDAC) invariably succumb to metastatic disease, but the underlying mechanisms that regulate PDAC cell movement and metastasis remain little understood. In this study, we investigated the effects of the chemokine gene CXCL12, which is silenced in PDAC tumors, yet is sufficient to suppress growth and metastasis when re-expressed. Chemokines like CXCL12 regulate cell movement in a biphasic pattern, with peak migration typically in the low nanomolar concentration range. Herein, we tested the hypothesis that the biphasic cell migration pattern induced by CXCL12 reflected a biased agonist bioenergetic signaling that might be exploited to interfere with PDAC metastasis. In human and murine PDAC cell models, we observed that nonmigratory doses of CXCL12 were sufficient to decrease oxidative phosphorylation and glycolytic capacity and to increase levels of phosphorylated forms of the master metabolic kinase AMPK. Those same doses of CXCL12 locked myosin light chain into a phosphorylated state, thereby decreasing F-actin polymerization and preventing cell migration in a manner dependent upon AMPK and the calcium-dependent kinase CAMKII. Notably, at elevated concentrations of CXCL12 that were insufficient to trigger chemotaxis of PDAC cells, AMPK blockade resulted in increased cell movement. In two preclinical mouse models of PDAC, administration of CXCL12 decreased tumor dissemination, supporting our hypothesis that chemokine-biased agonist signaling may offer a useful therapeutic strategy. Our results offer a mechanistic rationale for further investigation of CXCL12 as a potential therapy to prevent or treat PDAC metastasis.
Department of Microbiology & Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin.
Ishan
I
Roy
Department of Microbiology & Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin.
Donna M
DM
McAllister
Department of Microbiology & Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin.
Egal
E
Gorse
Department of Microbiology & Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin.
Kate
K
Dixon
Department of Microbiology & Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin.
Clinton T
CT
Piper
Department of Microbiology & Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin. MCW Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
Noah P
NP
Zimmerman
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin.
Anthony E
AE
Getschman
MCW Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin.
Susan
S
Tsai
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
Dannielle D
DD
Engle
MCW Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin.
Douglas B
DB
Evans
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin.
Brian F
BF
Volkman
Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin. MCW Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
Balaraman
B
Kalyanaraman
Department of Microbiology & Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin. MCW Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. mdwinell@mcw.edu.
Michael B
MB
Dwinell
D000091162:AMP-Activated Protein Kinase Kinases; D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000008:administration & dosage* / Q000378:metabolism; D006801:Humans; D051379:Mice; D009362:Neoplasm Metastasis; D010085:Oxidative Phosphorylation; D011494:Protein Kinases / Q000096:biosynthesis* / Q000378:metabolism
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases