Pancreatic cancer cell migration and metastasis is regulated by chemokine-biased agonism and bioenergetic signaling

Ishan Roy, Donna M. McAllister, Egal Gorse, Kate Dixon, Clinton T. Piper, Noah P. Zimmerman, Anthony E. Getschman, Susan Tsai, Dannielle D. Engle, Douglas B. Evans, Brian F. Volkman, Balaraman Kalyanaraman, Michael B. Dwinell

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3529-3542
Number of pages14
JournalCancer Research
Volume75
Issue number17
DOIs
StatePublished - Sep 1 2015
Externally publishedYes

Fingerprint

Pancreatic Neoplasms
Chemokines
Energy Metabolism
Cell Movement
Adenocarcinoma
Neoplasm Metastasis
Chemokine CXCL12
AMP-Activated Protein Kinases
Myosin Light Chains
Oxidative Phosphorylation
Chemotaxis
Polymerization
Actins
Neoplasms
Phosphotransferases
Calcium
Therapeutics
Growth
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Roy, I., McAllister, D. M., Gorse, E., Dixon, K., Piper, C. T., Zimmerman, N. P., ... Dwinell, M. B. (2015). Pancreatic cancer cell migration and metastasis is regulated by chemokine-biased agonism and bioenergetic signaling. Cancer Research, 75(17), 3529-3542. https://doi.org/10.1158/0008-5472.CAN-14-2645

Pancreatic cancer cell migration and metastasis is regulated by chemokine-biased agonism and bioenergetic signaling. / Roy, Ishan; McAllister, Donna M.; Gorse, Egal; Dixon, Kate; Piper, Clinton T.; Zimmerman, Noah P.; Getschman, Anthony E.; Tsai, Susan; Engle, Dannielle D.; Evans, Douglas B.; Volkman, Brian F.; Kalyanaraman, Balaraman; Dwinell, Michael B.

In: Cancer Research, Vol. 75, No. 17, 01.09.2015, p. 3529-3542.

Research output: Contribution to journalArticle

Roy, I, McAllister, DM, Gorse, E, Dixon, K, Piper, CT, Zimmerman, NP, Getschman, AE, Tsai, S, Engle, DD, Evans, DB, Volkman, BF, Kalyanaraman, B & Dwinell, MB 2015, 'Pancreatic cancer cell migration and metastasis is regulated by chemokine-biased agonism and bioenergetic signaling', Cancer Research, vol. 75, no. 17, pp. 3529-3542. https://doi.org/10.1158/0008-5472.CAN-14-2645
Roy, Ishan ; McAllister, Donna M. ; Gorse, Egal ; Dixon, Kate ; Piper, Clinton T. ; Zimmerman, Noah P. ; Getschman, Anthony E. ; Tsai, Susan ; Engle, Dannielle D. ; Evans, Douglas B. ; Volkman, Brian F. ; Kalyanaraman, Balaraman ; Dwinell, Michael B. / Pancreatic cancer cell migration and metastasis is regulated by chemokine-biased agonism and bioenergetic signaling. In: Cancer Research. 2015 ; Vol. 75, No. 17. pp. 3529-3542.
@article{b677fef37b3746e0b178c5d91e3e4b88,
title = "Pancreatic cancer cell migration and metastasis is regulated by chemokine-biased agonism and bioenergetic signaling",
abstract = "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.",
author = "Ishan Roy and McAllister, {Donna M.} and Egal Gorse and Kate Dixon and Piper, {Clinton T.} and Zimmerman, {Noah P.} and Getschman, {Anthony E.} and Susan Tsai and Engle, {Dannielle D.} and Evans, {Douglas B.} and Volkman, {Brian F.} and Balaraman Kalyanaraman and Dwinell, {Michael B.}",
year = "2015",
month = "9",
day = "1",
doi = "10.1158/0008-5472.CAN-14-2645",
language = "English (US)",
volume = "75",
pages = "3529--3542",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "17",

}

TY - JOUR

T1 - Pancreatic cancer cell migration and metastasis is regulated by chemokine-biased agonism and bioenergetic signaling

AU - Roy, Ishan

AU - McAllister, Donna M.

AU - Gorse, Egal

AU - Dixon, Kate

AU - Piper, Clinton T.

AU - Zimmerman, Noah P.

AU - Getschman, Anthony E.

AU - Tsai, Susan

AU - Engle, Dannielle D.

AU - Evans, Douglas B.

AU - Volkman, Brian F.

AU - Kalyanaraman, Balaraman

AU - Dwinell, Michael B.

PY - 2015/9/1

Y1 - 2015/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84942898695&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84942898695&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-14-2645

DO - 10.1158/0008-5472.CAN-14-2645

M3 - Article

C2 - 26330165

AN - SCOPUS:84942898695

VL - 75

SP - 3529

EP - 3542

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 17

ER -