Suppression of stromal-derived Dickkopf-3 (DKK3) inhibits tumor progression and prolongs survival in pancreatic ductal adenocarcinoma

Liran Zhou, Hongmei Husted, Todd Moore, Mason Lu, Defeng Deng, Yan Liu, Vijaya Ramachandran, Thiruvengadam Arumugam, Christof Niehrs, Huamin Wang, Paul Chiao, Jianhua Ling, Michael A. Curran, Anirban Maitra, Mien Chie Hung, Jeffrey E. Lee, Craig D. Logsdon, Rosa F. Hwang

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and it is unclear whether its stromal infiltrate contributes to its aggressiveness. Here, we demonstrate that Dickkopf-3 (DKK3) is produced by pancreatic stellate cells and is present in most human PDAC. DKK3 stimulates PDAC growth, metastasis, and resistance to chemotherapy with both paracrine and autocrine mechanisms through NF-B activation. Genetic ablation of DKK3 in an autochthonous model of PDAC inhibited tumor growth, induced a peritumoral infiltration of CD8+ T cells, and more than doubled survival. Treatment with a DKK3-blocking monoclonal antibody inhibited PDAC progression and chemoresistance and prolonged survival. The combination of DKK3 inhibition with immune checkpoint inhibition was more effective in reducing tumor growth than either treatment alone and resulted in a durable improvement in survival, suggesting that DKK3 neutralization may be effective as a single targeted agent or in combination with chemotherapy or immunotherapy for PDAC.

Original languageEnglish (US)
Article numbereaat3487
JournalScience Translational Medicine
Volume10
Issue number464
DOIs
StatePublished - Oct 24 2018

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Adenocarcinoma
Survival
Neoplasms
Pancreatic Stellate Cells
Growth
Blocking Antibodies
Combination Drug Therapy
Immunotherapy
Monoclonal Antibodies
Neoplasm Metastasis
T-Lymphocytes
Drug Therapy
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Suppression of stromal-derived Dickkopf-3 (DKK3) inhibits tumor progression and prolongs survival in pancreatic ductal adenocarcinoma. / Zhou, Liran; Husted, Hongmei; Moore, Todd; Lu, Mason; Deng, Defeng; Liu, Yan; Ramachandran, Vijaya; Arumugam, Thiruvengadam; Niehrs, Christof; Wang, Huamin; Chiao, Paul; Ling, Jianhua; Curran, Michael A.; Maitra, Anirban; Hung, Mien Chie; Lee, Jeffrey E.; Logsdon, Craig D.; Hwang, Rosa F.

In: Science Translational Medicine, Vol. 10, No. 464, eaat3487, 24.10.2018.

Research output: Contribution to journalArticle

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abstract = "Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and it is unclear whether its stromal infiltrate contributes to its aggressiveness. Here, we demonstrate that Dickkopf-3 (DKK3) is produced by pancreatic stellate cells and is present in most human PDAC. DKK3 stimulates PDAC growth, metastasis, and resistance to chemotherapy with both paracrine and autocrine mechanisms through NF-B activation. Genetic ablation of DKK3 in an autochthonous model of PDAC inhibited tumor growth, induced a peritumoral infiltration of CD8+ T cells, and more than doubled survival. Treatment with a DKK3-blocking monoclonal antibody inhibited PDAC progression and chemoresistance and prolonged survival. The combination of DKK3 inhibition with immune checkpoint inhibition was more effective in reducing tumor growth than either treatment alone and resulted in a durable improvement in survival, suggesting that DKK3 neutralization may be effective as a single targeted agent or in combination with chemotherapy or immunotherapy for PDAC.",
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AU - Zhou, Liran

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AU - Lu, Mason

AU - Deng, Defeng

AU - Liu, Yan

AU - Ramachandran, Vijaya

AU - Arumugam, Thiruvengadam

AU - Niehrs, Christof

AU - Wang, Huamin

AU - Chiao, Paul

AU - Ling, Jianhua

AU - Curran, Michael A.

AU - Maitra, Anirban

AU - Hung, Mien Chie

AU - Lee, Jeffrey E.

AU - Logsdon, Craig D.

AU - Hwang, Rosa F.

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N2 - Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and it is unclear whether its stromal infiltrate contributes to its aggressiveness. Here, we demonstrate that Dickkopf-3 (DKK3) is produced by pancreatic stellate cells and is present in most human PDAC. DKK3 stimulates PDAC growth, metastasis, and resistance to chemotherapy with both paracrine and autocrine mechanisms through NF-B activation. Genetic ablation of DKK3 in an autochthonous model of PDAC inhibited tumor growth, induced a peritumoral infiltration of CD8+ T cells, and more than doubled survival. Treatment with a DKK3-blocking monoclonal antibody inhibited PDAC progression and chemoresistance and prolonged survival. The combination of DKK3 inhibition with immune checkpoint inhibition was more effective in reducing tumor growth than either treatment alone and resulted in a durable improvement in survival, suggesting that DKK3 neutralization may be effective as a single targeted agent or in combination with chemotherapy or immunotherapy for PDAC.

AB - Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and it is unclear whether its stromal infiltrate contributes to its aggressiveness. Here, we demonstrate that Dickkopf-3 (DKK3) is produced by pancreatic stellate cells and is present in most human PDAC. DKK3 stimulates PDAC growth, metastasis, and resistance to chemotherapy with both paracrine and autocrine mechanisms through NF-B activation. Genetic ablation of DKK3 in an autochthonous model of PDAC inhibited tumor growth, induced a peritumoral infiltration of CD8+ T cells, and more than doubled survival. Treatment with a DKK3-blocking monoclonal antibody inhibited PDAC progression and chemoresistance and prolonged survival. The combination of DKK3 inhibition with immune checkpoint inhibition was more effective in reducing tumor growth than either treatment alone and resulted in a durable improvement in survival, suggesting that DKK3 neutralization may be effective as a single targeted agent or in combination with chemotherapy or immunotherapy for PDAC.

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