Early rhombic lip Protogenin+ve stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma

Abhirami Visvanathan; Olivier Saulnier; Chuan Chen; Parthiv Haldipur; Wilda Orisme; Alberto Delaidelli; Seungmin Shin; Jake Millman; Andrew Bryant; Namal Abeysundara; Xujia Wu; Liam D. Hendrikse; Vikas Patil; Zahedeh Bashardanesh; Joseph Golser; Bryn G. Livingston; Takuma Nakashima; Yusuke Funakoshi; Winnie Ong; Alexandra Rasnitsyn; Kimberly A. Aldinger; Cory M. Richman; Randy Van Ommeren; John J.Y. Lee; Michelle Ly; Maria C. Vladoiu; Kaitlin Kharas; Polina Balin; Anders W. Erickson; Vernon Fong; Jiao Zhang; Raúl A. Suárez; Hao Wang; Ning Huang; Jonelle G. Pallota; Tajana Douglas; Joonas Haapasalo; Ferechte Razavi; Evelina Silvestri; Olga Sirbu; Samantha Worme; Michelle M. Kameda-Smith; Xiaochong Wu; Craig Daniels; Antony K. MichaelRaj; Aparna Bhaduri; Daniel Schramek; Hiromichi Suzuki; Livia Garzia; Nabil Ahmed; Claudia L. Kleinman; Lincoln D. Stein; Peter Dirks; Christopher Dunham; Nada Jabado; Jeremy N. Rich; Wei Li; Poul H. Sorensen; Robert J. Wechsler-Reya; William A. Weiss; Kathleen J. Millen; David W. Ellison; Dimiter S. Dimitrov; Michael D. Taylor

doi:10.1016/j.cell.2024.06.011

Early rhombic lip Protogenin^+ve stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma

Abhirami Visvanathan, Olivier Saulnier, Chuan Chen, Parthiv Haldipur, Wilda Orisme, Alberto Delaidelli, Seungmin Shin, Jake Millman, Andrew Bryant, Namal Abeysundara, Xujia Wu, Liam D. Hendrikse, Vikas Patil, Zahedeh Bashardanesh, Joseph Golser, Bryn G. Livingston, Takuma Nakashima, Yusuke Funakoshi, Winnie Ong, Alexandra RasnitsynKimberly A. Aldinger, Cory M. Richman, Randy Van Ommeren, John J.Y. Lee, Michelle Ly, Maria C. Vladoiu, Kaitlin Kharas, Polina Balin, Anders W. Erickson, Vernon Fong, Jiao Zhang, Raúl A. Suárez, Hao Wang, Ning Huang, Jonelle G. Pallota, Tajana Douglas, Joonas Haapasalo, Ferechte Razavi, Evelina Silvestri, Olga Sirbu, Samantha Worme, Michelle M. Kameda-Smith, Xiaochong Wu, Craig Daniels, Antony K. MichaelRaj, Aparna Bhaduri, Daniel Schramek, Hiromichi Suzuki, Livia Garzia, Nabil Ahmed, Claudia L. Kleinman, Lincoln D. Stein, Peter Dirks, Christopher Dunham, Nada Jabado, Jeremy N. Rich, Wei Li, Poul H. Sorensen, Robert J. Wechsler-Reya, William A. Weiss, Kathleen J. Millen, David W. Ellison, Dimiter S. Dimitrov, Michael D. Taylor

Research output: Contribution to journal › Article › Scientific › peer-review

14 Citations (Scopus)

14 Downloads (Pure)

Abstract

We identify a population of Protogenin-positive (PRTG^+ve) MYC^high NESTIN^low stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RL^VZ). Oncogenic transformation of early Prtg^+ve rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG^+ve stem cells grow adjacent to a human-specific interposed vascular plexus in the RL^VZ, a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTG^high compartment of Gr3-MB in vivo using either the diphtheria toxin system or chimeric antigen receptor T cells constitutes effective therapy. Human Gr3-MBs likely arise from early embryonic RL^VZ PRTG^+ve stem cells inhabiting a specific perivascular niche. Targeting the PRTG^high compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB.

Original language	English
Pages (from-to)	4733-4750.e26
Number of pages	18
Journal	Cell
Volume	187
Issue number	17
DOIs	https://doi.org/10.1016/j.cell.2024.06.011
Publication status	Published - 2024
Publication type	A1 Journal article-refereed

Keywords

brain development
brain tumor immunotherapy
cancer genomics
group 3 medulloblastoma
perivascular niche
rhombic lip

Publication forum classification

Publication forum level 3

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cell.2024.06.011Licence: CC BY-NC

1-s2.0-S0092867424006512-main-3Final published version, 17.8 MBLicence: CC BY-NC

https://urn.fi/URN:NBN:fi:tuni-202408278327Licence: CC BY-NC

Cite this

Visvanathan, A., Saulnier, O., Chen, C., Haldipur, P., Orisme, W., Delaidelli, A., Shin, S., Millman, J., Bryant, A., Abeysundara, N., Wu, X., Hendrikse, L. D., Patil, V., Bashardanesh, Z., Golser, J., Livingston, B. G., Nakashima, T., Funakoshi, Y., Ong, W., ... Taylor, M. D. (2024). Early rhombic lip Protogenin^+ve stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma. Cell, 187(17), 4733-4750.e26. https://doi.org/10.1016/j.cell.2024.06.011

@article{71df1aa246de482492555a1e3e500c13,

title = "Early rhombic lip Protogenin+ve stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma",

abstract = "We identify a population of Protogenin-positive (PRTG+ve) MYChigh NESTINlow stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RLVZ). Oncogenic transformation of early Prtg+ve rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG+ve stem cells grow adjacent to a human-specific interposed vascular plexus in the RLVZ, a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTGhigh compartment of Gr3-MB in vivo using either the diphtheria toxin system or chimeric antigen receptor T cells constitutes effective therapy. Human Gr3-MBs likely arise from early embryonic RLVZ PRTG+ve stem cells inhabiting a specific perivascular niche. Targeting the PRTGhigh compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB.",

keywords = "brain development, brain tumor immunotherapy, cancer genomics, group 3 medulloblastoma, perivascular niche, rhombic lip",

author = "Abhirami Visvanathan and Olivier Saulnier and Chuan Chen and Parthiv Haldipur and Wilda Orisme and Alberto Delaidelli and Seungmin Shin and Jake Millman and Andrew Bryant and Namal Abeysundara and Xujia Wu and Hendrikse, \{Liam D.\} and Vikas Patil and Zahedeh Bashardanesh and Joseph Golser and Livingston, \{Bryn G.\} and Takuma Nakashima and Yusuke Funakoshi and Winnie Ong and Alexandra Rasnitsyn and Aldinger, \{Kimberly A.\} and Richman, \{Cory M.\} and \{Van Ommeren\}, Randy and Lee, \{John J.Y.\} and Michelle Ly and Vladoiu, \{Maria C.\} and Kaitlin Kharas and Polina Balin and Erickson, \{Anders W.\} and Vernon Fong and Jiao Zhang and Su{\'a}rez, \{Ra{\'u}l A.\} and Hao Wang and Ning Huang and Pallota, \{Jonelle G.\} and Tajana Douglas and Joonas Haapasalo and Ferechte Razavi and Evelina Silvestri and Olga Sirbu and Samantha Worme and Kameda-Smith, \{Michelle M.\} and Xiaochong Wu and Craig Daniels and MichaelRaj, \{Antony K.\} and Aparna Bhaduri and Daniel Schramek and Hiromichi Suzuki and Livia Garzia and Nabil Ahmed and Kleinman, \{Claudia L.\} and Stein, \{Lincoln D.\} and Peter Dirks and Christopher Dunham and Nada Jabado and Rich, \{Jeremy N.\} and Wei Li and Sorensen, \{Poul H.\} and Wechsler-Reya, \{Robert J.\} and Weiss, \{William A.\} and Millen, \{Kathleen J.\} and Ellison, \{David W.\} and Dimitrov, \{Dimiter S.\} and Taylor, \{Michael D.\}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

doi = "10.1016/j.cell.2024.06.011",

language = "English",

volume = "187",

pages = "4733--4750.e26",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "17",

}

Visvanathan, A, Saulnier, O, Chen, C, Haldipur, P, Orisme, W, Delaidelli, A, Shin, S, Millman, J, Bryant, A, Abeysundara, N, Wu, X, Hendrikse, LD, Patil, V, Bashardanesh, Z, Golser, J, Livingston, BG, Nakashima, T, Funakoshi, Y, Ong, W, Rasnitsyn, A, Aldinger, KA, Richman, CM, Van Ommeren, R, Lee, JJY, Ly, M, Vladoiu, MC, Kharas, K, Balin, P, Erickson, AW, Fong, V, Zhang, J, Suárez, RA, Wang, H, Huang, N, Pallota, JG, Douglas, T, Haapasalo, J, Razavi, F, Silvestri, E, Sirbu, O, Worme, S, Kameda-Smith, MM, Wu, X, Daniels, C, MichaelRaj, AK, Bhaduri, A, Schramek, D, Suzuki, H, Garzia, L, Ahmed, N, Kleinman, CL, Stein, LD, Dirks, P, Dunham, C, Jabado, N, Rich, JN, Li, W, Sorensen, PH, Wechsler-Reya, RJ, Weiss, WA, Millen, KJ, Ellison, DW, Dimitrov, DS & Taylor, MD 2024, 'Early rhombic lip Protogenin^+ve stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma', Cell, vol. 187, no. 17, pp. 4733-4750.e26. https://doi.org/10.1016/j.cell.2024.06.011

TY - JOUR

T1 - Early rhombic lip Protogenin+ve stem cells in a human-specific neurovascular niche initiate and maintain group 3 medulloblastoma

AU - Visvanathan, Abhirami

AU - Saulnier, Olivier

AU - Chen, Chuan

AU - Haldipur, Parthiv

AU - Orisme, Wilda

AU - Delaidelli, Alberto

AU - Shin, Seungmin

AU - Millman, Jake

AU - Bryant, Andrew

AU - Abeysundara, Namal

AU - Wu, Xujia

AU - Hendrikse, Liam D.

AU - Patil, Vikas

AU - Bashardanesh, Zahedeh

AU - Golser, Joseph

AU - Livingston, Bryn G.

AU - Nakashima, Takuma

AU - Funakoshi, Yusuke

AU - Ong, Winnie

AU - Rasnitsyn, Alexandra

AU - Aldinger, Kimberly A.

AU - Richman, Cory M.

AU - Van Ommeren, Randy

AU - Lee, John J.Y.

AU - Ly, Michelle

AU - Vladoiu, Maria C.

AU - Kharas, Kaitlin

AU - Balin, Polina

AU - Erickson, Anders W.

AU - Fong, Vernon

AU - Zhang, Jiao

AU - Suárez, Raúl A.

AU - Wang, Hao

AU - Huang, Ning

AU - Pallota, Jonelle G.

AU - Douglas, Tajana

AU - Haapasalo, Joonas

AU - Razavi, Ferechte

AU - Silvestri, Evelina

AU - Sirbu, Olga

AU - Worme, Samantha

AU - Kameda-Smith, Michelle M.

AU - Wu, Xiaochong

AU - Daniels, Craig

AU - MichaelRaj, Antony K.

AU - Bhaduri, Aparna

AU - Schramek, Daniel

AU - Suzuki, Hiromichi

AU - Garzia, Livia

AU - Ahmed, Nabil

AU - Kleinman, Claudia L.

AU - Stein, Lincoln D.

AU - Dirks, Peter

AU - Dunham, Christopher

AU - Jabado, Nada

AU - Rich, Jeremy N.

AU - Li, Wei

AU - Sorensen, Poul H.

AU - Wechsler-Reya, Robert J.

AU - Weiss, William A.

AU - Millen, Kathleen J.

AU - Ellison, David W.

AU - Dimitrov, Dimiter S.

AU - Taylor, Michael D.

PY - 2024

Y1 - 2024

N2 - We identify a population of Protogenin-positive (PRTG+ve) MYChigh NESTINlow stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RLVZ). Oncogenic transformation of early Prtg+ve rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG+ve stem cells grow adjacent to a human-specific interposed vascular plexus in the RLVZ, a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTGhigh compartment of Gr3-MB in vivo using either the diphtheria toxin system or chimeric antigen receptor T cells constitutes effective therapy. Human Gr3-MBs likely arise from early embryonic RLVZ PRTG+ve stem cells inhabiting a specific perivascular niche. Targeting the PRTGhigh compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB.

AB - We identify a population of Protogenin-positive (PRTG+ve) MYChigh NESTINlow stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RLVZ). Oncogenic transformation of early Prtg+ve rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG+ve stem cells grow adjacent to a human-specific interposed vascular plexus in the RLVZ, a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTGhigh compartment of Gr3-MB in vivo using either the diphtheria toxin system or chimeric antigen receptor T cells constitutes effective therapy. Human Gr3-MBs likely arise from early embryonic RLVZ PRTG+ve stem cells inhabiting a specific perivascular niche. Targeting the PRTGhigh compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB.

KW - brain development

KW - brain tumor immunotherapy

KW - cancer genomics

KW - group 3 medulloblastoma

KW - perivascular niche

KW - rhombic lip

U2 - 10.1016/j.cell.2024.06.011

DO - 10.1016/j.cell.2024.06.011

M3 - Article

C2 - 38971152

AN - SCOPUS:85198594814

SN - 0092-8674

VL - 187

SP - 4733-4750.e26

JO - Cell

JF - Cell

IS - 17

ER -