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

15 Citations (Scopus)

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. In addition to disseminating through the cerebrospinal fluid, medulloblastoma can metastasize through circulating tumor cells in the blood, thereby providing a different angle for clinical diagnosis and treatment development.

Original languageEnglish (US)
Pages (from-to)1050-1062.e14
JournalCell
Volume172
Issue number5
DOIs
StatePublished - Feb 22 2018
Externally publishedYes

Fingerprint

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

Keywords

  • brain tumors
  • circulating tumor cells
  • medulloblastoma
  • metastases
  • pediatric cancer

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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, KW, 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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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. In addition to disseminating through the cerebrospinal fluid, medulloblastoma can metastasize through circulating tumor cells in the blood, thereby providing a different angle for clinical diagnosis and treatment development.",
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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.

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KW - circulating tumor cells

KW - medulloblastoma

KW - metastases

KW - pediatric cancer

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