A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases

Livia Garzia, Noriyuki Kijima, A Sorana Morrissy, Pasqualino De Antonellis, Ana Guerreiro-Stucklin, Borja L Holgado, Xiaochong Wu, Xin Wang, Michael Parsons, Kory Zayne, Alex Manno, Claudia Kuzan-Fischer, Carolina Nor, Laura K Donovan, Jessica Liu, Lei Qin, Alexandra Garancher, Kun-Wei Liu, Sheila Mansouri, Betty LuuYuan Yao Thompson, Vijay Ramaswamy, John Peacock, Hamza Farooq, Patryk Skowron, David J H Shih, Angela Li, Sherine Ensan, Clinton S Robbins, Myron Cybulsky, Siddhartha Mitra, Yussanne Ma, Richard Moore, Andy Mungall, Yoon-Jae Cho, William A Weiss, Jennifer A Chan, Cynthia E Hawkins, Maura Massimino, Nada Jabado, Michal Zapotocky, David Sumerauer, Eric Bouffet, Peter Dirks, Uri Tabori, Poul H B Sorensen, Priscilla K Brastianos, Kenneth Aldape, Steven J M Jones, Marco A Marra, James R Woodgett, Robert J Wechsler-Reya, Daniel W Fults, Michael D Taylor

Research output: Contribution to journalArticle

Abstract

While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.

Original languageEnglish
Pages (from-to)1050-1062.e14
JournalCell
Volume172
Issue number5
DOIs
Publication statusPublished - Feb 22 2018

Keywords

  • Allografts
  • Animals
  • Cell Line, Tumor
  • Chemokine CCL2/metabolism
  • Chromosomes, Human, Pair 10/genetics
  • Female
  • Humans
  • Male
  • Medulloblastoma/blood supply
  • Meningeal Neoplasms/blood supply
  • Mice, SCID
  • Neoplastic Cells, Circulating
  • Parabiosis

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  • Cite this

    Garzia, L., Kijima, N., Morrissy, A. S., De Antonellis, P., Guerreiro-Stucklin, A., Holgado, B. L., Wu, X., Wang, X., Parsons, M., Zayne, K., Manno, A., Kuzan-Fischer, C., Nor, C., Donovan, L. K., Liu, J., Qin, L., Garancher, A., Liu, K-W., Mansouri, S., ... Taylor, M. D. (2018). A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases. Cell, 172(5), 1050-1062.e14. https://doi.org/10.1016/j.cell.2018.01.038