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L1CAM induces perineural invasion of pancreas cancer cells by upregulation of metalloproteinase expression

Oncogenevolume 38pages596608 (2019) | Download Citation

Abstract

Pancreas cancer cells have a tendency to invade along nerves. Such cancerous nerve invasion (CNI) is associated with poor outcome; however, the exact mechanism that drives cancer cells to disseminate along nerves is unknown. Immunohistochemical analysis of human pancreatic ductal adenocarcinoma (PDAC) specimens showed overexpression of the L1 cell adhesion molecule (L1CAM) in cancer cells and in adjacent Schwann cells (SC) in invaded nerves. By modeling the neural microenvironment, we found that L1CAM secreted from SCs acts as a strong chemoattractant to cancer cells, through activation of MAP kinase signaling. L1CAM also upregulated expression of metalloproteinase-2 (MMP-2) and MMP-9 by PDAC cells, through STAT3 activation. Using a transgenic Pdx-1-Cre/KrasG12D /p53R172H (KPC) mouse model, we show that treatment with anti-L1CAM Ab significantly reduces CNI in vivo. We provide evidence of a paracrine response between SCs and cancer cells in the neural niche, which promotes cancer invasion via L1CAM secretion.

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Additional information

These authors share co-seniorship: Moran Amit, Ziv Gil.

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Acknowledgements

Cindy Cohen is thanked for her editorial assistance. Nofar Rada is thanked for her artistic work. This study was supported by grants from the Israeli Science Foundation, Binational US-Israel Science Foundation, ICRF grant (Jacki and Bruce Barron cancer research scholars’ program and Barbara S Goodman research grant) and Israel Cancer Association.

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Affiliations

  1. The Laboratory for Applied Cancer Research, Head and Neck Center, Department of Otolaryngology Head and Neck Surgery, Clinical Research Institute at Rambam Healthcare Campus, Haifa, Israel

    • Shorook Na’ara
    • , Moran Amit
    •  & Ziv Gil
  2. Technion Integrated Cancer Center, Rappaport Institute of Medicine and Research, Technion, Israel Institute of Technology, Haifa, Israel

    • Ziv Gil

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The authors declare that they have no conflict of interest.

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Correspondence to Ziv Gil.

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https://doi.org/10.1038/s41388-018-0458-y