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Sci Transl Med. 2018 Oct 24;10(464). pii: eaat3487. doi: 10.1126/scitranslmed.aat3487.

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

Author information

1
Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2
Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
3
Division of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum (DKFZ), 69120 Heidelberg, Germany.
4
Institute of Molecular Biology (IMB), 55128 Mainz, Germany.
5
Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
6
Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
7
Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
8
Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. rhwang@mdanderson.org.
9
Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

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-κB 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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