TY - JOUR
T1 - Suppression of stromal-derived Dickkopf-3 (DKK3) inhibits tumor progression and prolongs survival in pancreatic ductal adenocarcinoma
AU - Zhou, Liran
AU - Husted, Hongmei
AU - Moore, Todd
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.
N1 - Publisher Copyright:
Copyright © 2018 The Authors.
PY - 2018/10/24
Y1 - 2018/10/24
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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U2 - 10.1126/scitranslmed.aat3487
DO - 10.1126/scitranslmed.aat3487
M3 - Article
C2 - 30355799
AN - SCOPUS:85055569272
SN - 1946-6234
VL - 10
JO - Science translational medicine
JF - Science translational medicine
IS - 464
M1 - eaat3487
ER -