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

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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References

  1. Bockman DE, Buchler M, Beger HG. Interaction of pancreatic ductal carcinoma with nerves leads to nerve damage. Gastroenterology. 1994;107:219–30.

    Article  CAS  Google Scholar 

  2. Swanson BJ, McDermott KM, Singh PK, Eggers JP, Crocker PR, Hollingsworth MA. MUC1 is a counter-receptor for myelin-associated glycoprotein (Siglec-4a) and their interaction contributes to adhesion in pancreatic cancer perineural invasion. Cancer Res. 2007;67:10222–9.

    Article  CAS  Google Scholar 

  3. Saloman JL, Albers KM, Li D, Hartman DJ, Crawford HC, Muha EA, et al. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer. Proc Natl Acad Sci USA. 2016;113:3078–83.

    Article  CAS  Google Scholar 

  4. Carter RL, Foster CS, Dinsdale EA, Pittam MR. Perineural spread by squamous carcinomas of the head and neck: a morphological study using antiaxonal and antimyelin monoclonal antibodies. J Clin Pathol. 1983;36:269–75.

    Article  CAS  Google Scholar 

  5. Maru N, Ohori M, Kattan MW, Scardino PT, Wheeler TM. Prognostic significance of the diameter of perineural invasion in radical prostatectomy specimens. Hum Pathol. 2001;32:828–33.

    Article  CAS  Google Scholar 

  6. Takahashi T, Ishikura H, Motohara T, Okushiba S, Dohke M, Katoh H. Perineural invasion by ductal adenocarcinoma of the pancreas. J Surg Oncol. 1997;65:164–70.

    Article  CAS  Google Scholar 

  7. Demir IE, Ceyhan GO, Liebl F, D’Haese JG, Maak M, Friess H. Neural invasion in pancreatic cancer: the past, present and future. Cancers. 2010;2:1513–27. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3837319&tool=pmcentrez&rendertype=abstract Accessed 7 sept 2014.

  8. Stopczynski RE, Normolle DP, Hartman DJ, Ying H, DeBerry JJ, Bielefeldt K, et al. Neuroplastic changes occur early in the development of pancreatic ductal adenocarcinoma. Cancer Res. 2014;74:1718–27.

    Article  CAS  Google Scholar 

  9. Amit M, Na’ara S, Gil Z. Mechanisms of cancer dissemination along nerves. Nat Rev Cancer. 2016;16:399–408.

    Article  CAS  Google Scholar 

  10. Lahoud MJ, Kourie HR, Antoun J, El Osta L, Ghosn M. Road map for pain management in pancreatic cancer: a review. World J Gastrointest Oncol. 2016;8:599–606.

    Article  Google Scholar 

  11. Gavert N, Ben-Shmuel A, Raveh S, Ben-Ze’ev A. L1-CAM in cancerous tissues. Expert Opin Biol Ther. 2008;8:1749–57.

    Article  CAS  Google Scholar 

  12. Schafer MKE, Altevogt P. L1CAM malfunction in the nervous system and human carcinomas. Cell Mol Life Sci. 2010;67:2425–37.

    Article  Google Scholar 

  13. Silletti S, Yebra M, Perez B, Cirulli V, McMahon M, Montgomery AMP. Extracellular signal-regulated kinase (ERK)-dependent gene expression contributes to L1 cell adhesion molecule-dependent motility and invasion. J Biol Chem. 2004;279:28880–8.

    Article  CAS  Google Scholar 

  14. Bergmann F, Wandschneider F, Sipos B, Moldenhauer G, Schniewind B, Welsch T. et al. Elevated L1CAMexpression in precursor lesions and primary and metastastic tissues of pancreatic ductal adenocarcinoma. Oncol Rep. 2010;4:909–15.

    Google Scholar 

  15. Mechtersheimer S, Gutwein P.Agmon-Levin N, Stoeck a, Oleszewski M, Riedle S, et al. Ectodomain shedding of L1 adhesion molecule promotes cell migration by autocrine binding to integrins. J Cell Biol. 2001;155:661–73 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2198870&tool=pmcentrez&rendertype=abstract Accessed 15 Oct 2014.

  16. Webber C, Zochodne D. The nerve regenerative microenvironment: early behavior and partnership of axons and Schwann cells. Exp Neurol. 2010;223:51–9.

    Article  CAS  Google Scholar 

  17. Deborde S, Omelchenko T, Lyubchik A, Zhou Y, He S, McNamara WF, et al. Schwann cells induce cancer cell dispersion and invasion. J Clin Invest. 2016;126:1538–54.

    Article  Google Scholar 

  18. Demir IE, Boldis A, Pfitzinger PL, Teller S, Brunner E, Klose N, et al. Investigation of Schwann cells at neoplastic cell sites before the onset of cancer invasion. J Natl Cancer Inst. 2014;106. http://www.ncbi.nlm.nih.gov/pubmed/25106646 Accessed 11 Sept. 2014.

  19. Guo K, Ma Q, Li J, Wang Z, Shan T, Li W, et al. Interaction of the sympathetic nerve with pancreatic cancer cells promotes perineural invasion through the activation of STAT3 signaling. Mol Cancer Ther. 2013;12:264–73.

    Article  CAS  Google Scholar 

  20. Gil Z, Cavel O, Kelly K, Brader P, Rein A, Gao SP, et al. Paracrine regulation of pancreatic cancer cell invasion by peripheral nerves. J Natl Cancer Inst. 2010;102:107–18.

    Article  CAS  Google Scholar 

  21. Na’ara S, Gil Z, Amit M. In vitro modeling of cancerous neural invasion: the dorsal root ganglion model. J Vis Exp. 2016;110:e52990.

    Google Scholar 

  22. Colombo F, Racchetti G, Meldolesi J. Neurite outgrowth induced by NGF or L1CAM via activation of the TrkA receptor is sustained also by the exocytosis of enlargeosomes. Proc Natl Acad Sci USA. 2014;111:16943–8.

    Article  CAS  Google Scholar 

  23. Huang X, Hu J, Li Y, Zhuyun Yang Z, Zhu H, Zhou L, et al. The cell adhesion molecule L1 regulates the expression of FGF21 and enhances neurite outgrowth. Brain Res. 2013;1530:13–21.

    Article  CAS  Google Scholar 

  24. Brummendorf T, Kenwrick S, Rathjen FG. Neural cell recognition molecule L1: from cell biology to human hereditary brain malformations. Curr Opin Neurobiol. 1998;8:87–97.

    Article  CAS  Google Scholar 

  25. Ben Q-W, Wang J-C, Liu J, Zhu Y, Yuan F, Yao W-Y, et al. Positive expression of L1-CAM is associated with perineural invasion and poor outcome in pancreatic ductal adenocarcinoma. Ann Surg Oncol. 2010;17:2213–21.

    Article  Google Scholar 

  26. Kaifi JT, Zinnkann U, Yekebas EF, Schurr PG, Reichelt U, Wachowiak R, et al. L1 is a potential marker for poorly-differentiated pancreatic neuroendocrine carcinoma. World J Gastroenterol. 2006;12:94–8.

    Article  CAS  Google Scholar 

  27. Geismann C, Morscheck M, Koch D, Bergmann F, Ungefroren H, Arlt A, et al. Up-regulation of L1CAM in pancreatic duct cells is transforming growth factor beta1- and slug-dependent: role in malignant transformation of pancreatic cancer. Cancer Res. 2009;69:4517–26.

    Article  CAS  Google Scholar 

  28. Maretzky T, Schulte M, Ludwig A, Rose-John S, Blobel C, Hartmann D, et al. L1 is sequentially processed by two differently activated metalloproteases and presenilin/gamma-secretase and regulates neural cell adhesion, cell migration, and neurite outgrowth. Mol Cell Biol. 2005;25:9040–53.

    Article  CAS  Google Scholar 

  29. Riedle S, Kiefel H, Gast D, Bondong S, Wolterink S, Gutwein P, et al. Nuclear translocation and signalling of L1-CAM in human carcinoma cells requires ADAM10 and presenilin/gamma-secretase activity. Biochem J. 2009;420:391–402.

    Article  CAS  Google Scholar 

  30. Hauser S, Bickel L, Weinspach D, Gerg M, Schafer MK, Pfeifer M, et al. Full-length L1CAM and not its Delta2Delta27 splice variant promotes metastasis through induction of gelatinase expression. PLoS ONE. 2011;6:e18989.

    Article  CAS  Google Scholar 

  31. Weinspach D, Seubert B, Schaten S, Honert K, Sebens S, Altevogt P, et al. Role of L1 cell adhesion molecule (L1CAM) in the metastatic cascade: promotion of dissemination, colonization, and metastatic growth. Clin Exp Metastas. 2014;31:87–100.

    Article  CAS  Google Scholar 

  32. Apte MV, Park S, Phillips PA, Santucci N, Goldstein D, Kumar RK, et al. Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas. 2004;29:179–87.

    Article  CAS  Google Scholar 

  33. Cavel O, Shomron O, Shabtay A, Vital J, Trejo-Leider L, Weizman N, et al. Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor. Cancer Res. 2012;72:5733–43.

    Article  CAS  Google Scholar 

  34. Torres MP, Rachagani S, Souchek JJ, Mallya K, Johansson SL, Batra SK. Novel pancreatic cancer cell lines derived from genetically engineered mouse models of spontaneous pancreatic adenocarcinoma: applications in diagnosis and therapy. PLoS ONE. 2013;8:e80580.

    Article  Google Scholar 

  35. Amit M, Na’ara S, Leider-Trejo L, Binenbaum Y, Kulish N, Fridman E. et al. Upregulation of RET inducesperineurial invasion of pancreatic adenocarcinoma. Oncogene. 2017;36:3232–3239.

    Article  CAS  Google Scholar 

  36. Abiatari I, Gillen S, DeOliveira T, Klose T, Bo K, Giese NA, et al. The microtubule-associated protein MAPRE2 is involved in perineural invasion of pancreatic cancer cells. Int J Oncol. 2009;35:1111–6.

    CAS  PubMed  Google Scholar 

  37. Dai H, Li R, Wheeler T, Ozen M, Ittmann M, Anderson M, et al. Enhanced survival in perineural invasion of pancreatic cancer: an in vitro approach. Hum Pathol. 2007;38:299–307.

    Article  CAS  Google Scholar 

  38. Demir IE, Friess H, Ceyhan GO. Nerve-cancer interactions in the stromal biology of pancreatic cancer. Front Physiol. 2012;3:97.

    Article  Google Scholar 

  39. He S, Chen C-H, Chernichenko N, He S, Bakst RL, Barajas F, et al. GFRalpha1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling. Proc Natl Acad Sci USA. 2014;111:E2008–17.

    Article  CAS  Google Scholar 

  40. Bapat AA, Munoz RM, Von Hoff DD, Han H. Blocking nerve growth factor signaling reduces the neural invasion potential of pancreatic cancer cells. PLoS ONE. 2016;11:e0165586.

    Article  Google Scholar 

  41. Roh J, Muelleman T, Tawfik O, Thomas SM. Perineural growth in head and neck squamous cell carcinoma: a review. Oral Oncol. 2015;51:16–23.

    Article  Google Scholar 

  42. Ceyhan GO, Giese NA, Erkan M, Kerscher AG, Wente MN, Giese T, et al. The neurotrophic factor artemin promotes pancreatic cancer invasion. Ann Surg. 2006;244:274–81.

    Article  Google Scholar 

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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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Correspondence to Ziv Gil.

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

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Na’ara, S., Amit, M. & Gil, Z. L1CAM induces perineural invasion of pancreas cancer cells by upregulation of metalloproteinase expression. Oncogene 38, 596–608 (2019). https://doi.org/10.1038/s41388-018-0458-y

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