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Theranostics 2019; 9(2):324-336. doi:10.7150/thno.28201 This issue Cite

Research Paper

β-catenin-activated autocrine PDGF/Src signaling is a therapeutic target in pancreatic cancer

Tzu-Lei Kuo¹, Kuang-Hung Cheng², Yan-Shen Shan^3,4, Li-Tzong Chen^1,5,6, Wen-Chun Hung^1,6✉

1. National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan
2. Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
3. Institute of Clinical Medicine, National Cheng Kung University, Tainan 704, Taiwan
4. Department of Surgery, National Cheng Kung University Hospital, Tainan 704, Taiwan
5. Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
6. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 804, Taiwan

✉ Corresponding author: Dr. Wen-Chun Hung, National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan. Tel: 886-6-7000123 Fax: 886-6-2083427 E-mail: hung1228org.tw

Abstract

K-ras mutation and p53 loss are the most prevalent genetic alterations in pancreatic cancer. In addition to these two alterations, pancreatic tumors frequently contain a third genetic defect. Mutations in the WNT/ß-catenin signaling molecules occur in 15-20% of pancreatic cancer patients and co-exist with K-ras mutation and p53 loss. However, the contribution of the WNT/ß-catenin pathway in pancreatic tumorigenesis is still unclear.

Methods: We generated Pdx1-CreKras^G12Dp53^L/+APC^L/+ (KPA) mice and compared their phenotypes with Pdx1-CreKras^G12Dp53^L/+ (KPC) mice. The signaling pathways specifically activated in the KPA mice were investigated and the therapeutic effect by targeting the activated pathways was evaluated. We finally validated our findings in human blood and tumor samples.

Results: Survival of the KPA mice was shorter than that of the KPC mice. The KPA cancer cells are highly invasive and exhibit distorted morphology in organoid culture with extensive invadopodia formation and elevated matrix metalloproteinase (MMP) activity. The platelet-derived growth factor (PDGF) pathway is upregulated in the KPA cancer cells, and PDGF production induced by ß-catenin triggers constitutive activation of the Src kinase via the PDGF receptor in the cells. Serum PDGF concentration of the KPA mice is much higher than that of the normal and KPC mice. The Src inhibitor dasatinib effectively inhibits tumor growth and metastasis of the KPA cancer cells. Patient's serum PDGF level is significantly correlated with the expression of PDGF and phosphor-Src in tumors and elevated PDGF/phosphor-Src level in tumors predicts increased recurrence and poor survival. Moreover, mutations of the WNT/ß-catenin signaling molecules are higher in patients with elevated PDGF/phosphor-Src level.

Conclusion: ß-catenin activation, coupled with K-ras mutation and p53 loss, activates an autocrine PDGF/Src signaling in pancreatic cancer and defines a subset of patients who might be sensitive to Src inhibition. In addition, serum PDGF level could be a reliable biomarker for patient selection in clinic.

Keywords: β-catenin, platelet-derived growth factor (PDGF), Src kinase, metastasis, pancreatic cancer

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