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 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^*

^*Tämän työn vastaava kirjoittaja

Tutkimustuotos: Artikkeli › Tieteellinen › vertaisarvioitu

22 Sitaatiot (Scopus)

14 Lataukset (Pure)

Abstrakti

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.

Alkuperäiskieli	Englanti
Sivut	4733-4750.e26
Sivumäärä	18
Julkaisu	Cell
Vuosikerta	187
Numero	17
DOI - pysyväislinkit	https://doi.org/10.1016/j.cell.2024.06.011
Tila	Julkaistu - 2024
OKM-julkaisutyyppi	A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä

Rahoitus

M.D.T. is a CPRIT Scholar in Cancer Research (CPRIT - RR220051). M.D.T. is the Cyvia and Melvyn Wolff Chair of Pediatric Neuro-Oncology, Texas Children's Cancer and Hematology Center. M.D.T. is supported by the NIH (R01NS106155, R01CA159859, and R01CA255369), the Pediatric Brain Tumor Foundation, the Terry Fox Research Institute, the Canadian Institutes of Health Research, the Cure Search Foundation, the Matthew Larson Foundation (IronMatt), b.r.a.i.n.child, Meagan's Walk, the Swifty Foundation, the Brain Tumour Charity, Genome Canada, Genome BC, Genome Quebec, the Ontario Research Fund, Worldwide Cancer Research, the V Foundation for Cancer Research, and the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. M.D.T. is also supported by a Canadian Cancer Society Research Institute Impact grant, a Cancer Research UK Brain Tumour Award, 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. was supported by the Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children and the University of Toronto. The authors thank Ben Pakuts for graphic design support. A.V. O. Saulnier, and C.C. designed, performed, and analyzed most of the experiments in this study. P.H. contributed to in situ hybridization and interpretation. W. Orisme and A.D. contributed to staining of medulloblastoma patient samples. W.L. provided peptide library. J.M. and J.G. contributed to in situ hybridization. W. Ong and M.C.V. contributed to single-cell preparation. A.R. contributed to SCENIC workflow. T.N. and Y.F. contributed to tissue data collection. L.D.H. contributed to scRNA-seq analysis. B.L. N.A. and V.F. contributed to imaging. J.Y.L. C.R. and J.H. contributed to in vivo experiments. V.P. contributed to RNA-seq analysis. S.S. Xujia Wu, R.V.O. M.L. K.K. P.B. A.E. J.Z. M.K.S. and O. Sirbu contributed to experiments. Z.B. and A.B. contributed to human CS12 analysis. R.S. H.W. N.H. J.P. and T.D. contributed to in vivo experiments. F.R. and E.S. provided human samples. K.A.A. A.K.M. L.G. C.L.K. L.D.S. P.D. R.W.R. N.J. W.W. J.R. H.S. D.S. D.E. and K.J.M. provided expert advice. Xiaochong Wu and C.D. provided reagents and expert advice. D.S.D. and M.D.T. jointly supervised the project. A.V. O. Saulnier, C.C. and M.D.T. prepared the figures and wrote the manuscript. The authors declare no competing interests. A patent related to this work was submitted by University of Pittsburgh (University Docket No. 05700/F&R ref. 48881-0028P01), US 63/275,326, \u201CMolecules that bind to Protogenin polypeptides.\u201D M.D.T. is a CPRIT Scholar in Cancer Research. M.D.T. is supported by the NIH ( R01NS106155 , R01CA159859 , and R01CA255369 ), the Pediatric Brain Tumor Foundation , the Terry Fox Research Institute , the Canadian Institutes of Health Research , the Cure Search Foundation , the Matthew Larson Foundation (IronMatt), b.r.a.i.n.child, Meagan\u2019s Walk , the Swifty Foundation , the Brain Tumour Charity, Genome Canada, Genome BC, Genome Quebec , the Ontario Research Foundation , Worldwide Cancer Research , the V Foundation for Cancer Research , and the Ontario Institute for Cancer Research through funding provided by the Government of Ontario . M.D.T. is also supported by a Canadian Cancer Society Research Institute Impact grant, a Cancer Research UK Brain Tumour Award , a Stand Up To Cancer St. Baldrick\u2019s 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 also supported by the Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children and the University of Toronto . The authors thank Ben Pakuts for graphic design support.

Rahoittajat	Rahoittajan numero
V Foundation for Cancer Research
Swifty Foundation
Ontario Institute for Cancer Research
E.S.
Government of Canada
Genome Canada
Ontario Research Foundation
University of Toronto
Brain Tumour Charity
Entertainment Industry Foundation
American Association for Cancer Research
Stand Up To Cancer
Canadian Cancer Society
Brain Tumour Award
SU2C) St. Baldrick's Pediatric Dream Team Translational Research
Texas Children's Cancer and Hematology Center
Pediatric Brain Tumor Foundation
Worldwide Cancer Research
Matthew Larson Foundation
Ontario Government
Royal Hospital for Sick Children
Canadian Institutes of Health Research
Cure Search Foundation
Genome British Columbia
Terry Fox Research Institute
CPRIT	CPRIT - RR220051
University of Pittsburgh	05700/F, US 63/275,326, 48881-0028P01
SU2C Canada Cancer Stem Cell Dream Team Research Funding	SU2C-AACR-DT-19-15
NIH	R01NS106155, R01CA255369, R01CA159859
Stand Up To Cancer St. Baldrick’s Pediatric Dream Team Translational Research	SU2C-AACR-DT1113

YK:n kestävän kehityksen tavoitteet

Tämä tuotos edistää seuraavia kestävän kehityksen tavoitteita:

SDG 3 – Hyvä terveys ja hyvinvointi

Julkaisufoorumi-taso

Jufo-taso 3

!!ASJC Scopus subject areas

Yleinen biokemia, genetiikka ja molekyylibiologia

Pääsy asiakirjaan

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

1-s2.0-S0092867424006512-main-3Final published version, 17,8 MBLisenssi: CC BY-NC

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

Siteeraa tätä

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",

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, Vuosikerta 187, Nro 17, Sivut 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 -