Research ArticleCancer

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

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Science Translational Medicine  24 Oct 2018:
Vol. 10, Issue 464, eaat3487
DOI: 10.1126/scitranslmed.aat3487

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Killing tumors by targeting their neighbors

Pancreatic cancer is infamous for its bad prognosis, as well as for its dense stroma. Most therapies target the tumor cells themselves rather than the stroma, but now, Zhou et al. identified a therapeutic target called DKK3, which is produced by pancreatic stellate cells. The authors showed that this protein was present in most of the human pancreatic tumors in their study sample. They also demonstrated the effectiveness of ablating DKK3, either by genetic means or with a monoclonal antibody. The antibody treatment reduced tumor growth and extended survival in mouse models, especially when combined with an immune checkpoint inhibitor, demonstrating its therapeutic potential.

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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