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

Oncogene
Shorook Na'araZiv Gil

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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Citations

Jun 30, 2019·Cancers·Giulia GaspariniMassimo Falconi
Nov 23, 2019·British Journal of Cancer·Takashi IchikawaMasato Kusunoki
Jun 21, 2020·Nature Reviews. Gastroenterology & Hepatology·Ihsan Ekin Demir, Carmen Mota Reyes
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Feb 18, 2020·Frontiers in Oncology·Ting HuangYudong Wang
Nov 21, 2020·Annals of Surgical Oncology·Shohei YoshiyaMasaki Mori
Jan 5, 2021·Frontiers in Cell and Developmental Biology·Wenjun WangJiuwei Cui
Jan 23, 2021·Neuroscience Letters·Patrick J HuntMoran Amit
Nov 11, 2020·International Journal of Molecular Sciences·Fanny M DeschepperPaula A Videira
Jan 10, 2021·International Journal of Molecular Sciences·Griselda A Cabral-PachecoMargarita L Martinez-Fierro
Dec 19, 2020·Cancer Research·Deborah A SilvermanMoran Amit
Apr 11, 2021·Biochemical Pharmacology·Michelle Melgarejo da RosaMoacyr Jesus Barreto de Melo Rego
May 5, 2021·Biochimica Et Biophysica Acta. Reviews on Cancer·Kavita MallyaManeesh Jain

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Methods Mentioned

BETA
immunoprecipitation
confocal microscopy
transfection
transgenic
FCS
electrophoresis
pancreatectomy

Software Mentioned

Image J
Fiji
Origin
ImageJ

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