Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell

Gerda Kildisiute; Waleed M. Kholosy; Matthew D. Young; Kenny Roberts; Rasa Elmentaite; Sander R. van Hooff; Clarissa N. Pacyna; Eleonora Khabirova; Alice Piapi; Christine Thevanesan; Eva Bugallo-Blanco; Christina Burke; Lira Mamanova; Kaylee M. Keller; Karin P.S. Langenberg-Ververgaert; Philip Lijnzaad; Thanasis Margaritis; Frank C.P. Holstege; Michelle L. Tas; Marc H.W.A. Wijnen; Max M. van Noesel; Ignacio del Valle; Giuseppe Barone; Reinier van der Linden; Catriona Duncan; John Anderson; John C. Achermann; Muzlifah Haniffa; Sarah A. Teichmann; Dyanne Rampling; Neil J. Sebire; Xiaoling He; Ronald R. de Krijger; Roger A. Barker; Kerstin B. Meyer; Omer Bayraktar; Karin Straathof; Jan J. Molenaar; Sam Behjati

doi:10.1126/sciadv.abd3311

Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell

Gerda Kildisiute, Waleed M. Kholosy, Matthew D. Young, Kenny Roberts, Rasa Elmentaite, Sander R. van Hooff, Clarissa N. Pacyna, Eleonora Khabirova, Alice Piapi, Christine Thevanesan, Eva Bugallo-Blanco, Christina Burke, Lira Mamanova, Kaylee M. Keller, Karin P.S. Langenberg-Ververgaert, Philip Lijnzaad, Thanasis Margaritis, Frank C.P. Holstege, Michelle L. Tas, Marc H.W.A. WijnenMax M. van Noesel, Ignacio del Valle, Giuseppe Barone, Reinier van der Linden, Catriona Duncan, John Anderson, John C. Achermann, Muzlifah Haniffa, Sarah A. Teichmann, Dyanne Rampling, Neil J. Sebire, Xiaoling He, Ronald R. de Krijger, Roger A. Barker, Kerstin B. Meyer, Omer Bayraktar, Karin Straathof, Jan J. Molenaar, Sam Behjati^*

^*Corresponding author for this work

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

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Abstract

Neuroblastoma is a childhood cancer that resembles developmental stages of the neural crest. It is not established what developmental processes neuroblastoma cancer cells represent. Here, we sought to reveal the phenotype of neuroblastoma cancer cells by comparing cancer (n = 19,723) with normal fetal adrenal single-cell transcriptomes (n = 57,972). Our principal finding was that the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients, and clinical phenotypes. We substantiated our findings in 650 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that a pan-neuroblastoma cancer cell state exists, which may be attractive for novel immunotherapeutic and targeted avenues.

Original language	English
Article number	eabd3311
Pages (from-to)	1-13
Journal	Science advances
Volume	7
Issue number	6
DOIs	https://doi.org/10.1126/sciadv.abd3311
Publication status	Published - 5 Feb 2021

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sciadv.abd3311Final published version, 11.2 MBLicence: CC BY

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Kildisiute, G., Kholosy, W. M., Young, M. D., Roberts, K., Elmentaite, R., van Hooff, S. R., Pacyna, C. N., Khabirova, E., Piapi, A., Thevanesan, C., Bugallo-Blanco, E., Burke, C., Mamanova, L., Keller, K. M., Langenberg-Ververgaert, K. P. S., Lijnzaad, P., Margaritis, T., Holstege, F. C. P., Tas, M. L., ... Behjati, S. (2021). Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell. Science advances, 7(6), 1-13. Article eabd3311. https://doi.org/10.1126/sciadv.abd3311

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title = "Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell",

abstract = "Neuroblastoma is a childhood cancer that resembles developmental stages of the neural crest. It is not established what developmental processes neuroblastoma cancer cells represent. Here, we sought to reveal the phenotype of neuroblastoma cancer cells by comparing cancer (n = 19,723) with normal fetal adrenal single-cell transcriptomes (n = 57,972). Our principal finding was that the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients, and clinical phenotypes. We substantiated our findings in 650 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that a pan-neuroblastoma cancer cell state exists, which may be attractive for novel immunotherapeutic and targeted avenues.",

author = "Gerda Kildisiute and Kholosy, {Waleed M.} and Young, {Matthew D.} and Kenny Roberts and Rasa Elmentaite and {van Hooff}, {Sander R.} and Pacyna, {Clarissa N.} and Eleonora Khabirova and Alice Piapi and Christine Thevanesan and Eva Bugallo-Blanco and Christina Burke and Lira Mamanova and Keller, {Kaylee M.} and Langenberg-Ververgaert, {Karin P.S.} and Philip Lijnzaad and Thanasis Margaritis and Holstege, {Frank C.P.} and Tas, {Michelle L.} and Wijnen, {Marc H.W.A.} and {van Noesel}, {Max M.} and {del Valle}, Ignacio and Giuseppe Barone and {van der Linden}, Reinier and Catriona Duncan and John Anderson and Achermann, {John C.} and Muzlifah Haniffa and Teichmann, {Sarah A.} and Dyanne Rampling and Sebire, {Neil J.} and Xiaoling He and {de Krijger}, {Ronald R.} and Barker, {Roger A.} and Meyer, {Kerstin B.} and Omer Bayraktar and Karin Straathof and Molenaar, {Jan J.} and Sam Behjati",

note = "Funding Information: Informed consent for research was obtained from participants (or their carers). Studies underlying this paper have received appropriate approval by ethics review boards as per national legislation. Dutch tumor samples were obtained through an institutionally approved research study. U.K. tumor samples were collected under the following studies: National Health Service (NHS) National Research Ethics Service reference 16/EE/0394 (tumor samples) and NHS National Research Ethics Service reference 96/085 (fetal tissues). Additional fetal tissue was provided by the Joint Medical Research Council (MRC)/Wellcome Trust–funded (grant #099175/Z/12/Z) Human Developmental Biology Resource (HDBR; www.hdbr.org) (10), with appropriate maternal written consent and approval from the Newcastle and North Tyneside NHS Health Authority Joint Ethics Committee. HDBR is regulated by the U.K. Human Tissue Authority (HTA; www.hta.gov.uk) and operates in accordance with the relevant HTA Codes of Practice. Funding Information: This study was funded by the Wellcome Trust (references 110104/Z/15/Z, 206194, 211276/Z/18/Z, 211276/C/18/Z, 102803/Z/13/Z, and 209328/Z/17/Z). Additional funding was received from the St. Baldrick's Foundation (Robert J. Arceci Award to S.B.), NIHR (Great Ormond Street Biomedical Research Centre), ERC-START grant PREDICT-716079, NWO-Vidi grant 91716482, H2020-iPC-826121 grant, and National Institute for Health Research (NIHR 146281) Cambridge Biomedical Research Centre. Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).",

year = "2021",

month = feb,

day = "5",

doi = "10.1126/sciadv.abd3311",

language = "English",

volume = "7",

pages = "1--13",

number = "6",

}

Kildisiute, G, Kholosy, WM, Young, MD, Roberts, K, Elmentaite, R, van Hooff, SR, Pacyna, CN, Khabirova, E, Piapi, A, Thevanesan, C, Bugallo-Blanco, E, Burke, C, Mamanova, L, Keller, KM, Langenberg-Ververgaert, KPS, Lijnzaad, P, Margaritis, T, Holstege, FCP, Tas, ML, Wijnen, MHWA , van Noesel, MM, del Valle, I, Barone, G, van der Linden, R, Duncan, C, Anderson, J, Achermann, JC, Haniffa, M, Teichmann, SA, Rampling, D, Sebire, NJ, He, X, de Krijger, RR, Barker, RA, Meyer, KB, Bayraktar, O, Straathof, K, Molenaar, JJ & Behjati, S 2021, 'Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell', Science advances, vol. 7, no. 6, eabd3311, pp. 1-13. https://doi.org/10.1126/sciadv.abd3311

TY - JOUR

T1 - Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell

AU - Kildisiute, Gerda

AU - Kholosy, Waleed M.

AU - Young, Matthew D.

AU - Roberts, Kenny

AU - Elmentaite, Rasa

AU - van Hooff, Sander R.

AU - Pacyna, Clarissa N.

AU - Khabirova, Eleonora

AU - Piapi, Alice

AU - Thevanesan, Christine

AU - Bugallo-Blanco, Eva

AU - Burke, Christina

AU - Mamanova, Lira

AU - Keller, Kaylee M.

AU - Langenberg-Ververgaert, Karin P.S.

AU - Lijnzaad, Philip

AU - Margaritis, Thanasis

AU - Holstege, Frank C.P.

AU - Tas, Michelle L.

AU - Wijnen, Marc H.W.A.

AU - van Noesel, Max M.

AU - del Valle, Ignacio

AU - Barone, Giuseppe

AU - van der Linden, Reinier

AU - Duncan, Catriona

AU - Anderson, John

AU - Achermann, John C.

AU - Haniffa, Muzlifah

AU - Teichmann, Sarah A.

AU - Rampling, Dyanne

AU - Sebire, Neil J.

AU - He, Xiaoling

AU - de Krijger, Ronald R.

AU - Barker, Roger A.

AU - Meyer, Kerstin B.

AU - Bayraktar, Omer

AU - Straathof, Karin

AU - Molenaar, Jan J.

AU - Behjati, Sam

N1 - Funding Information: Informed consent for research was obtained from participants (or their carers). Studies underlying this paper have received appropriate approval by ethics review boards as per national legislation. Dutch tumor samples were obtained through an institutionally approved research study. U.K. tumor samples were collected under the following studies: National Health Service (NHS) National Research Ethics Service reference 16/EE/0394 (tumor samples) and NHS National Research Ethics Service reference 96/085 (fetal tissues). Additional fetal tissue was provided by the Joint Medical Research Council (MRC)/Wellcome Trust–funded (grant #099175/Z/12/Z) Human Developmental Biology Resource (HDBR; www.hdbr.org) (10), with appropriate maternal written consent and approval from the Newcastle and North Tyneside NHS Health Authority Joint Ethics Committee. HDBR is regulated by the U.K. Human Tissue Authority (HTA; www.hta.gov.uk) and operates in accordance with the relevant HTA Codes of Practice. Funding Information: This study was funded by the Wellcome Trust (references 110104/Z/15/Z, 206194, 211276/Z/18/Z, 211276/C/18/Z, 102803/Z/13/Z, and 209328/Z/17/Z). Additional funding was received from the St. Baldrick's Foundation (Robert J. Arceci Award to S.B.), NIHR (Great Ormond Street Biomedical Research Centre), ERC-START grant PREDICT-716079, NWO-Vidi grant 91716482, H2020-iPC-826121 grant, and National Institute for Health Research (NIHR 146281) Cambridge Biomedical Research Centre. Publisher Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

PY - 2021/2/5

Y1 - 2021/2/5

N2 - Neuroblastoma is a childhood cancer that resembles developmental stages of the neural crest. It is not established what developmental processes neuroblastoma cancer cells represent. Here, we sought to reveal the phenotype of neuroblastoma cancer cells by comparing cancer (n = 19,723) with normal fetal adrenal single-cell transcriptomes (n = 57,972). Our principal finding was that the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients, and clinical phenotypes. We substantiated our findings in 650 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that a pan-neuroblastoma cancer cell state exists, which may be attractive for novel immunotherapeutic and targeted avenues.

AB - Neuroblastoma is a childhood cancer that resembles developmental stages of the neural crest. It is not established what developmental processes neuroblastoma cancer cells represent. Here, we sought to reveal the phenotype of neuroblastoma cancer cells by comparing cancer (n = 19,723) with normal fetal adrenal single-cell transcriptomes (n = 57,972). Our principal finding was that the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients, and clinical phenotypes. We substantiated our findings in 650 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that a pan-neuroblastoma cancer cell state exists, which may be attractive for novel immunotherapeutic and targeted avenues.

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DO - 10.1126/sciadv.abd3311

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VL - 7

SP - 1

EP - 13

JO - Science advances

JF - Science advances

IS - 6

M1 - eabd3311

ER -

Tumor to normal single-cell mRNA comparisons reveal a pan-neuroblastoma cancer cell

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