KLF10 loss in the pancreas provokes activation of SDF-1 and induces distant metastases of pancreatic ductal adenocarcinoma in the Kras(G12D) p53(flox/flox) model

C-C Weng, J R Hawse, M Subramaniam, V H S Chang, W C Y Yu, W-C Hung, L-T Chen, K-H Cheng

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5 Citations (Scopus)

Abstract

Krüppel-like transcription factor 10 (KLF10), also named as TIEG1, plays essential roles in mediating transforming growth factor beta (TGFβ) signaling and has been shown to function as a tumor suppressor in multiple cancer types. However, its roles in mediating cancer progression in vivo have yet to be fully characterized. Here, we have employed two well-characterized Pdx-1CreLSL-Kras(G12D) and Pdx-1CreLSL-Kras(G12D)p53(L/L) pancreatic cancer models to ablate KLF10 expression and determine the impact of KLF10 deletion on tumor development and progression. We show that loss of KLF10 cooperates with Kras(G12D) leading to an invasive and widely metastatic phenotype of pancreatic ductal adenocarcinoma (PDAC). Mechanistically, loss of KLF10 in PDAC is shown to increase distant metastases and cancer stemness through activation of SDF-1/CXCR4 and AP-1 pathways. Furthermore, we demonstrate that targeting the SDF-1/CXCR4 pathway in the context of KLF10 deletion substantially suppresses PDAC progression suggesting that inhibition of this pathway represents a novel therapeutic strategy for PDAC treatment.

Original languageEnglish
Pages (from-to)5532-5543
Number of pages12
JournalOncogene
Volume36
Issue number39
DOIs
Publication statusPublished - Sep 28 2017

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Keywords

  • Animals
  • Carcinoma, Pancreatic Ductal
  • Chemokine CXCL12
  • Early Growth Response Transcription Factors
  • Humans
  • Kruppel-Like Transcription Factors
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Metastasis
  • Pancreatic Neoplasms
  • Proto-Oncogene Proteins p21(ras)
  • Signal Transduction
  • Survival Rate
  • Tumor Suppressor Protein p53
  • Journal Article

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