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

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-KrasG12Dp53L/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 KrasG12D 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.

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Acknowledgements

This work was supported by grants MOST 104-2320-B-110-003 and 105-2320 -B-110-004 (to KH Cheng), MOST 101-2628-B-400-003-MY2 (to LT Chen) and MOST 105-2321-B-400-010 (to LT Chen and KH Cheng) from the Ministry of Science and Technology, Taiwan ROC, and grants KMU-TP104G00, KMU-TP105G00 (to KH Cheng) from Kaohsiung Medical University, Kaohsiung, Taiwan, and grant R01 DE14036 (to JRH and MS) from the National Institutes of Health, USA.

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Weng, CC., Hawse, J., Subramaniam, M. et al. KLF10 loss in the pancreas provokes activation of SDF-1 and induces distant metastases of pancreatic ductal adenocarcinoma in the KrasG12D p53flox/flox model. Oncogene 36, 5532–5543 (2017). https://doi.org/10.1038/onc.2017.155

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