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 Luu; Yuan 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

doi:10.1016/j.cell.2018.01.038

A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases

Cell. 2018 Feb 22;172(5):1050-1062.e14. doi: 10.1016/j.cell.2018.01.038.

Authors

Livia Garzia¹, Noriyuki Kijima¹, A Sorana Morrissy¹, Pasqualino De Antonellis¹, Ana Guerreiro-Stucklin¹, Borja L Holgado¹, Xiaochong Wu¹, Xin Wang², Michael Parsons³, Kory Zayne¹, Alex Manno¹, Claudia Kuzan-Fischer¹, Carolina Nor¹, Laura K Donovan¹, Jessica Liu¹, Lei Qin¹, Alexandra Garancher⁴, Kun-Wei Liu⁴, Sheila Mansouri⁵, Betty Luu¹, Yuan Yao Thompson², Vijay Ramaswamy⁶, John Peacock¹, Hamza Farooq², Patryk Skowron², David J H Shih², Angela Li⁷, Sherine Ensan⁷, Clinton S Robbins⁸, Myron Cybulsky⁹, Siddhartha Mitra¹⁰, Yussanne Ma¹¹, Richard Moore¹¹, Andy Mungall¹¹, Yoon-Jae Cho¹², William A Weiss¹³, Jennifer A Chan¹⁴, Cynthia E Hawkins¹⁵, Maura Massimino¹⁶, Nada Jabado¹⁷, Michal Zapotocky¹⁸, David Sumerauer¹⁹, Eric Bouffet⁶, Peter Dirks²⁰, Uri Tabori²¹, Poul H B Sorensen²², Priscilla K Brastianos²³, Kenneth Aldape⁵, Steven J M Jones¹¹, Marco A Marra¹¹, James R Woodgett³, Robert J Wechsler-Reya²⁴, Daniel W Fults²⁵, Michael D Taylor²⁶

Affiliations

¹ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
² Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
³ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
⁴ Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
⁵ MacFeeters-Hamilton Brain Tumour Centre, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
⁶ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
⁷ Department of Immunology, University of Toronto, Toronto, ON, Canada.
⁸ Department of Immunology, University of Toronto, Toronto, ON, Canada; Peter Munk Cardiac Centre, Toronto General Research Institute, University Health Network, Toronto, ON, Canada.
⁹ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Toronto General Research Institute, University Health Network, Toronto, ON, Canada.
¹⁰ Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.
¹¹ Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency and Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
¹² Departments of Pediatrics, Neurological Surgery and Neurology, University of California, San Francisco, San Francisco, CA, USA.
¹³ Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada.
¹⁴ Division of Pathology, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁵ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Division of Pathology, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁶ Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
¹⁷ Division of Hematology/Oncology, McGill University, Montreal, QC, Canada.
¹⁸ Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic.
¹⁹ Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic.
²⁰ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada.
²¹ The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada.
²² Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
²³ Division of Neuro-Oncology, Massachusetts General Hospital, Boston, MA, USA.
²⁴ Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA; Department of Pediatrics, University of California, San Diego, San Diego, CA, USA.
²⁵ Department of Neurosurgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
²⁶ Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada; The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada. Electronic address: mdtaylor@sickkids.ca.

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.

Keywords: brain tumors; circulating tumor cells; medulloblastoma; metastases; pediatric cancer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

CCL2 protein, human
Chemokine CCL2

Abstract

Publication types

MeSH terms

Substances

Grants and funding