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 & 34 others 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

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

Fingerprint

Medulloblastoma
Tumors
Neoplasm Metastasis
Cells
Cerebrospinal fluid
Circulating Neoplastic Cells
Chemokine CCL2
Brain
Blood
Parabiosis
Tissue
Heterologous Transplantation
Cell- and Tissue-Based Therapy
Cerebrospinal Fluid
Neoplasms
Spinal Cord
Morbidity
Mortality
Research

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

Cite this

Garzia, L., Kijima, N., Morrissy, A. S., De Antonellis, P., Guerreiro-Stucklin, A., Holgado, B. L., ... 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

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

In: Cell, Vol. 172, No. 5, 22.02.2018, p. 1050-1062.e14.

Research output: Contribution to journalArticle

Garzia, L, Kijima, N, Morrissy, AS, De Antonellis, P, Guerreiro-Stucklin, A, Holgado, BL, Wu, X, Wang, X, Parsons, M, Zayne, K, Manno, A, Kuzan-Fischer, C, Nor, C, Donovan, LK, Liu, J, Qin, L, Garancher, A, Liu, K-W, Mansouri, S, Luu, B, Thompson, YY, Ramaswamy, V, Peacock, J, Farooq, H, Skowron, P, Shih, DJH, Li, A, Ensan, S, Robbins, CS, Cybulsky, M, Mitra, S, Ma, Y, Moore, R, Mungall, A, Cho, Y-J, Weiss, WA, Chan, JA, Hawkins, CE, Massimino, M, Jabado, N, Zapotocky, M, Sumerauer, D, Bouffet, E, Dirks, P, Tabori, U, Sorensen, PHB, Brastianos, PK, Aldape, K, Jones, SJM, Marra, MA, Woodgett, JR, Wechsler-Reya, RJ, Fults, DW & Taylor, MD 2018, 'A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases', Cell, vol. 172, no. 5, pp. 1050-1062.e14. https://doi.org/10.1016/j.cell.2018.01.038
Garzia L, Kijima N, Morrissy AS, De Antonellis P, Guerreiro-Stucklin A, Holgado BL et al. A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases. Cell. 2018 Feb 22;172(5):1050-1062.e14. https://doi.org/10.1016/j.cell.2018.01.038
Garzia, Livia ; Kijima, Noriyuki ; Morrissy, A Sorana ; De Antonellis, Pasqualino ; Guerreiro-Stucklin, Ana ; Holgado, Borja L ; Wu, Xiaochong ; Wang, Xin ; Parsons, Michael ; Zayne, Kory ; Manno, Alex ; Kuzan-Fischer, Claudia ; Nor, Carolina ; Donovan, Laura K ; Liu, Jessica ; Qin, Lei ; Garancher, Alexandra ; Liu, Kun-Wei ; Mansouri, Sheila ; Luu, Betty ; Thompson, Yuan Yao ; Ramaswamy, Vijay ; Peacock, John ; Farooq, Hamza ; Skowron, Patryk ; Shih, David J H ; Li, Angela ; Ensan, Sherine ; Robbins, Clinton S ; Cybulsky, Myron ; Mitra, Siddhartha ; Ma, Yussanne ; Moore, Richard ; Mungall, Andy ; Cho, Yoon-Jae ; Weiss, William A ; Chan, Jennifer A ; Hawkins, Cynthia E ; Massimino, Maura ; Jabado, Nada ; Zapotocky, Michal ; Sumerauer, David ; Bouffet, Eric ; Dirks, Peter ; Tabori, Uri ; Sorensen, Poul H B ; Brastianos, Priscilla K ; Aldape, Kenneth ; Jones, Steven J M ; Marra, Marco A ; Woodgett, James R ; Wechsler-Reya, Robert J ; Fults, Daniel W ; Taylor, Michael D. / A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases. In: Cell. 2018 ; Vol. 172, No. 5. pp. 1050-1062.e14.
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title = "A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases",
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.",
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TY - JOUR

T1 - A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases

AU - Garzia, Livia

AU - Kijima, Noriyuki

AU - Morrissy, A Sorana

AU - De Antonellis, Pasqualino

AU - Guerreiro-Stucklin, Ana

AU - Holgado, Borja L

AU - Wu, Xiaochong

AU - Wang, Xin

AU - Parsons, Michael

AU - Zayne, Kory

AU - Manno, Alex

AU - Kuzan-Fischer, Claudia

AU - Nor, Carolina

AU - Donovan, Laura K

AU - Liu, Jessica

AU - Qin, Lei

AU - Garancher, Alexandra

AU - Liu, Kun-Wei

AU - Mansouri, Sheila

AU - Luu, Betty

AU - Thompson, Yuan Yao

AU - Ramaswamy, Vijay

AU - Peacock, John

AU - Farooq, Hamza

AU - Skowron, Patryk

AU - Shih, David J H

AU - Li, Angela

AU - Ensan, Sherine

AU - Robbins, Clinton S

AU - Cybulsky, Myron

AU - Mitra, Siddhartha

AU - Ma, Yussanne

AU - Moore, Richard

AU - Mungall, Andy

AU - Cho, Yoon-Jae

AU - Weiss, William A

AU - Chan, Jennifer A

AU - Hawkins, Cynthia E

AU - Massimino, Maura

AU - Jabado, Nada

AU - Zapotocky, Michal

AU - Sumerauer, David

AU - Bouffet, Eric

AU - Dirks, Peter

AU - Tabori, Uri

AU - Sorensen, Poul H B

AU - Brastianos, Priscilla K

AU - Aldape, Kenneth

AU - Jones, Steven J M

AU - Marra, Marco A

AU - Woodgett, James R

AU - Wechsler-Reya, Robert J

AU - Fults, Daniel W

AU - Taylor, Michael D

N1 - Copyright © 2018 Elsevier Inc. All rights reserved.

PY - 2018/2/22

Y1 - 2018/2/22

N2 - 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.

AB - 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.

KW - Allografts

KW - Animals

KW - Cell Line, Tumor

KW - Chemokine CCL2/metabolism

KW - Chromosomes, Human, Pair 10/genetics

KW - Female

KW - Humans

KW - Male

KW - Medulloblastoma/blood supply

KW - Meningeal Neoplasms/blood supply

KW - Mice, SCID

KW - Neoplastic Cells, Circulating

KW - Parabiosis

U2 - 10.1016/j.cell.2018.01.038

DO - 10.1016/j.cell.2018.01.038

M3 - Article

VL - 172

SP - 1050-1062.e14

JO - Cell

JF - Cell

SN - 0092-8674

IS - 5

ER -