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

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 journal › Article › peer-review

47 Scopus citations

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 language	English (US)
Pages (from-to)	1050-1062.e14
Journal	Cell
Volume	172
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2018.01.038
State	Published - Feb 22 2018
Externally published	Yes

Keywords

brain tumors
circulating tumor cells
medulloblastoma
metastases
pediatric cancer

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

Access to Document

10.1016/j.cell.2018.01.038

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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

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, YJ, 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

@article{8a58c20e959343d283a7b83ec4f12ffe,

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. 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.",

keywords = "brain tumors, circulating tumor cells, medulloblastoma, metastases, pediatric cancer",

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

note = "Funding Information: We would like to thank S. Archer for technical writing and C. Smith for artwork. M.D.T. is supported by the NIH (R01CA148699 and R01CA159859), The Pediatric Brain Tumour Foundation, The Terry Fox Research Institute, The Canadian Institutes of Health Research, The Cure Search Foundation, b.r.a.i.n.child, Meagan's Walk, Genome Canada, Genome BC, and the Ontario Institute for Cancer Research. M.D.T. is also supported by a Canadian Cancer Society Research Institute Impact grant and by a Stand Up To Cancer (SU2C) St. Baldrick's Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113) and SU2C Canada Cancer Stem Cell Dream Team Research Funding (SU2C-AACR-DT-19-15) provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, with supplementary support from the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. M.D.T. is supported by the Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children and the University of Toronto. L.G. was supported by the Davis M. Ferguson Memorial Fund at ABTA. Alex's Lemonade Stand Young Investigator Award supported V.R. P.D.A. was supported by AIRC iCare research fellowship. This study was conducted with the support of the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. V.R. is supported by a CIHR fellowship and an Alberta Innovates - Health Solutions Clinical Fellowship. The Huntsman Cancer Foundation 25182 supports D.W.F. Funding Information: We would like to thank S. Archer for technical writing and C. Smith for artwork. M.D.T. is supported by the NIH ( R01CA148699 and R01CA159859 ), The Pediatric Brain Tumour Foundation , The Terry Fox Research Institute , The Canadian Institutes of Health Research , The Cure Search Foundation , b.r.a.i.n.child , Meagan{\textquoteright}s Walk , Genome Canada , Genome BC , and the Ontario Institute for Cancer Research . M.D.T. is also supported by a Canadian Cancer Society Research Institute Impact grant and by a Stand Up To Cancer (SU2C) St. Baldrick{\textquoteright}s Pediatric Dream Team Translational Research Grant ( SU2C-AACR-DT1113 ) and SU2C Canada Cancer Stem Cell Dream Team Research Funding ( SU2C-AACR-DT-19-15 ) provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research , with supplementary support from the Ontario Institute for Cancer Research through funding provided by the Government of Ontario . Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. M.D.T. is supported by the Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children and the University of Toronto . L.G. was supported by the Davis M. Ferguson Memorial Fund at ABTA. Alex{\textquoteright}s Lemonade Stand Young Investigator Award supported V.R. P.D.A. was supported by AIRC iCare research fellowship . This study was conducted with the support of the Ontario Institute for Cancer Research through funding provided by the Government of Ontario . V.R. is supported by a CIHR fellowship and an Alberta Innovates - Health Solutions Clinical Fellowship. The Huntsman Cancer Foundation 25182 supports D.W.F. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2018",

month = feb,

day = "22",

doi = "10.1016/j.cell.2018.01.038",

language = "English (US)",

volume = "172",

pages = "1050--1062.e14",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "5",

}

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 - Funding Information: We would like to thank S. Archer for technical writing and C. Smith for artwork. M.D.T. is supported by the NIH (R01CA148699 and R01CA159859), The Pediatric Brain Tumour Foundation, The Terry Fox Research Institute, The Canadian Institutes of Health Research, The Cure Search Foundation, b.r.a.i.n.child, Meagan's Walk, Genome Canada, Genome BC, and the Ontario Institute for Cancer Research. M.D.T. is also supported by a Canadian Cancer Society Research Institute Impact grant and by a Stand Up To Cancer (SU2C) St. Baldrick's Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113) and SU2C Canada Cancer Stem Cell Dream Team Research Funding (SU2C-AACR-DT-19-15) provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, with supplementary support from the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. M.D.T. is supported by the Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children and the University of Toronto. L.G. was supported by the Davis M. Ferguson Memorial Fund at ABTA. Alex's Lemonade Stand Young Investigator Award supported V.R. P.D.A. was supported by AIRC iCare research fellowship. This study was conducted with the support of the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. V.R. is supported by a CIHR fellowship and an Alberta Innovates - Health Solutions Clinical Fellowship. The Huntsman Cancer Foundation 25182 supports D.W.F. Funding Information: We would like to thank S. Archer for technical writing and C. Smith for artwork. M.D.T. is supported by the NIH ( R01CA148699 and R01CA159859 ), The Pediatric Brain Tumour Foundation , The Terry Fox Research Institute , The Canadian Institutes of Health Research , The Cure Search Foundation , b.r.a.i.n.child , Meagan’s Walk , Genome Canada , Genome BC , and the Ontario Institute for Cancer Research . M.D.T. is also supported by a Canadian Cancer Society Research Institute Impact grant and by a Stand Up To Cancer (SU2C) St. Baldrick’s Pediatric Dream Team Translational Research Grant ( SU2C-AACR-DT1113 ) and SU2C Canada Cancer Stem Cell Dream Team Research Funding ( SU2C-AACR-DT-19-15 ) provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research , with supplementary support from the Ontario Institute for Cancer Research through funding provided by the Government of Ontario . Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. M.D.T. is supported by the Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children and the University of Toronto . L.G. was supported by the Davis M. Ferguson Memorial Fund at ABTA. Alex’s Lemonade Stand Young Investigator Award supported V.R. P.D.A. was supported by AIRC iCare research fellowship . This study was conducted with the support of the Ontario Institute for Cancer Research through funding provided by the Government of Ontario . V.R. is supported by a CIHR fellowship and an Alberta Innovates - Health Solutions Clinical Fellowship. The Huntsman Cancer Foundation 25182 supports D.W.F. Publisher Copyright: © 2018 Elsevier Inc.

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. 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.

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. 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.

KW - brain tumors

KW - circulating tumor cells

KW - medulloblastoma

KW - metastases

KW - pediatric cancer

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DO - 10.1016/j.cell.2018.01.038

M3 - Article

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SN - 0092-8674

VL - 172

SP - 1050-1062.e14

JO - Cell

JF - Cell

IS - 5

ER -

A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases

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Keywords

ASJC Scopus subject areas

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