KLF10 loss in the pancreas provokes activation of SDF-1 and induces distant metastases of pancreatic ductal adenocarcinoma in the KrasG12D p53flox/flox model

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

Research output: Contribution to journalArticle

4 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-KrasG12D and Pdx-1CreLSL-KrasG12D p53L/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 (US)
Pages (from-to)5532-5543
Number of pages12
JournalOncogene
Volume36
Issue number39
DOIs
StatePublished - Sep 28 2017

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Pancreas
Adenocarcinoma
Transcription Factors
Neoplasm Metastasis
Neoplasms
Transcription Factor AP-1
Pancreatic Neoplasms
Transforming Growth Factor beta
Phenotype
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

KLF10 loss in the pancreas provokes activation of SDF-1 and induces distant metastases of pancreatic ductal adenocarcinoma in the KrasG12D p53flox/flox model. / Weng, C. C.; Hawse, John R; Subramaniam, M.; Chang, V. H.S.; Yu, W. C.Y.; Hung, W. C.; Chen, L. T.; Cheng, K. H.

In: Oncogene, Vol. 36, No. 39, 28.09.2017, p. 5532-5543.

Research output: Contribution to journalArticle

Weng, C. C. ; Hawse, John R ; Subramaniam, M. ; Chang, V. H.S. ; Yu, W. C.Y. ; Hung, W. C. ; Chen, L. T. ; Cheng, K. H. / KLF10 loss in the pancreas provokes activation of SDF-1 and induces distant metastases of pancreatic ductal adenocarcinoma in the KrasG12D p53flox/flox model. In: Oncogene. 2017 ; Vol. 36, No. 39. pp. 5532-5543.
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