TY - JOUR
T1 - L1CAM induces perineural invasion of pancreas cancer cells by upregulation of metalloproteinase expression
AU - Na’ara, Shorook
AU - Amit, Moran
AU - Gil, Ziv
N1 - Funding Information:
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.
Publisher Copyright:
© 2018, Springer Nature Limited.
PY - 2019/1/24
Y1 - 2019/1/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85053307046&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053307046&partnerID=8YFLogxK
U2 - 10.1038/s41388-018-0458-y
DO - 10.1038/s41388-018-0458-y
M3 - Article
C2 - 30171263
AN - SCOPUS:85053307046
SN - 0950-9232
VL - 38
SP - 596
EP - 608
JO - Oncogene
JF - Oncogene
IS - 4
ER -