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

Theranostics
Tzu-Lei KuoWen-Chun Hung

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-CreKrasG12Dp53L/+APCL/+ (KPA) mice and compared their phenotypes with Pdx1-CreKrasG12Dp53L/+ (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...Continue Reading

Citations

May 30, 2019·Cancers·Tzu-Lei KuoWen-Chun Hung
Apr 24, 2020·Frontiers in Pharmacology·Jia ZhangJiang-Jiang Qin
Jan 23, 2021·Critical Reviews in Oncology/hematology·Yan LuoRui Kong
Nov 13, 2020·Frontiers in Cell and Developmental Biology·Ilenia MasiLaura Rosanò
Nov 21, 2020·International Journal of Molecular Sciences·Justin F CreedenRobert E McCullumsmith

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immunoprecipitation assay
biopsy

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