The therapeutic targeting of the FGFR1/Src/NF-κB signaling axis inhibits pancreatic ductal adenocarcinoma stemness and oncogenicity

Abstract

The aberrant activation of the FGFR signaling is detected in many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), suggesting it as a potential therapeutic target. In this study, we investigated the antitumor and anti-metastasis efficacy of the selective FGFR1 inhibitor, PD173074 in PDAC. We used immunohistochemical and in situ hybridization analyses to demonstrate a strong correlation between FGFR1 amplification and/or expression and disease progression in PDAC patients. We showed that ALDHhigh (ALDH+) pancreatic cancer cells exhibited stem cell-like phenotype and expressed higher levels of FGFR1, Src, NF-κB, alongside stemness markers like Oct4 and Sox2, compared to their ALDHlow/null (ALDH−) counterparts, suggesting the preferential activation of the FGFR1/Src/NF-κB signaling axis in pancreatic cancer stem cells (panCSCs). Furthermore, treatment of the ALDHhigh/ FGFR1-rich pancreatic cancer cell lines with PD173074, a selective FGFR1 inhibitor, revealed that PD173074 inhibited the proliferation and self-renewal of the panCSCs, and induced their apoptosis by activating caspase-3 and cleaving Poly-ADP ribose Polymerase (PARP). The anti-CSCs effect of PD173074 was associated with decreased expression of Oct4, Sox-2, Nanog, and c-Myc, as well as suppression of XIAP, Bcl2, and survivin expression, dose-dependently. Additionally, activation of cMet, Src, ERK 1/2 and NFκB (p65) was also inhibited by PD173074. Also, of clinical relevance, the disruption of the FGFR1/Src/NF-κB signaling axis positively correlated with poor clinical prognosis among the PDAC patients. We concluded that PD173074 suppresses the tumorigenesis and CSCs-like phenotype of PDAC cells, highlighting its therapeutic efficacy and providing support for its potential use as a therapeutic option for the ‘difficult-to-treat’, ‘quick-to-relapse’ PDAC patients.

Graphical Abstract

Schematic abstract showing how PD173074 inhibits PDAC growth through selective targeting of FGFR1, suppression of cancer stemness, disruption of the FGFR1/Src/NF-κB signaling axis and activation of the cell death signaling pathway.

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Data Availability

The datasets used and analyzed in the current study are available from the corresponding author in response to reasonable requests.

Change history

  • 04 January 2019

    In the original publication, the affiliations of authors were published incorrectly. The corrected affiliations are given in this Correction.

  • 04 January 2019

    In the original publication, the affiliations of authors were published incorrectly. The corrected affiliations are given in this Correction.

Abbreviations

PDAC:

Pancreatic ductal adenocarcinoma

GEM:

Gemcitabine

CSCs:

Cancer stem cells

CAP:

Capecitabine

panCSCs:

Pancreatic cancer stem cells

FGFR1:

Fibroblast growth factor receptor 1

ABCG2:

ATP-binding cassette transporters

TCA:

Trichloroacetic acid

H&E:

Hematoxylin and eosin

VEGFRs:

Vascular endothelial growth factor

FGFR:

Fibroblast growth factor receptor

PDGFR:

Platelet-derived growth factor receptors

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Funding

This work was supported by National Science Council of Taiwan: Tsu-Yi Chao (MOST103-2325-B-038-002 and MOST105-2314-B038-080), and Wei-Hwa Lee (MOST 105-2320-B-038-054). This study was also supported by Grants from Taipei Medical University (105TMU-SHH-15) to Wei-Hwa Lee and grants from Taipei Medical University -National Taiwan University of Science and Technology Joint Research Program (TMU-NTUST-103-03) to Chi-Tai Yeh. Grants from Tri-Service General Hospital Penghu Branch, Penghu, Taiwan (TSGH-PH-105-3, TSGH-PH-106-4) to Shiue-Wei Lai.

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Authors

Contributions

Conceived and designed the study: SWL, OAB, CTY, TYC. Performed the experiments: SWL. Analyzed the data: SWL, OAB, CTY, TYC. Wrote the paper: SWL, OAB. Provided reagents, materials, and experimental infrastructure: WHL, CTY, TYC. All authors read and approved the definitive version of the manuscript.

Corresponding authors

Correspondence to Chi-Tai Yeh or Tsu-Yi Chao.

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Conflict of interest

All authors are working for either university or hospitals. We claim that we do not have any actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three years of beginning the work submitted that could inappropriately influence our work.

Ethics approval

This study was conducted in a cohort of patients with pancreatic cancer who underwent pancreaticoduodenectomy at Tri-Service General Hospital, Taipei, Taiwan between January 2000 and December 2013. A predesigned data collection format was used to review the patients’ medical records for evaluation of clinicopathologic characteristics and survival outcomes. The study was reviewed and approved by the institute review board (TSGHIRB 2-104-05-040).

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Lai, S., Bamodu, O.A., Tsai, W. et al. The therapeutic targeting of the FGFR1/Src/NF-κB signaling axis inhibits pancreatic ductal adenocarcinoma stemness and oncogenicity. Clin Exp Metastasis 35, 663–677 (2018). https://doi.org/10.1007/s10585-018-9919-5

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Keywords

  • Pancreatic cancer
  • FGFR1
  • PD173074
  • Selective inhibitor
  • Cancer stem cells
  • ALDH
  • FGFR1/Src/NF-κB signaling