Single cell derived mRNA signals across human kidney tumors
Young, Matthew D.; Mitchell, Thomas J.; Custers, Lars; Margaritis, Thanasis; Morales-Rodriguez, Francisco; Kwakwa, Kwasi; Khabirova, Eleonora; Kildisiute, Gerda; Oliver, Thomas R.W.; de Krijger, Ronald R.; van den Heuvel-Eibrink, Marry M.; Comitani, Federico; Piapi, Alice; Bugallo-Blanco, Eva; Thevanesan, Christine; Burke, Christina; Prigmore, Elena; Ambridge, Kirsty; Roberts, Kenny; Braga, Felipe A.Vieira; Coorens, Tim H.H.; Del Valle, Ignacio; Wilbrey-Clark, Anna; Mamanova, Lira; Stewart, Grant D.; Gnanapragasam, Vincent J.; Rampling, Dyanne; Sebire, Neil; Coleman, Nicholas; Hook, Liz; Warren, Anne; Haniffa, Muzlifah; Kool, Marcel; Pfister, Stefan M.; Achermann, John C.; He, Xiaoling; Barker, Roger A.; Shlien, Adam; Bayraktar, Omer A.; Teichmann, Sarah A.; Holstege, Frank C.; Meyer, Kerstin B.; Drost, Jarno; Straathof, Karin; Behjati, Sam
(2021) Nature Communications, volume 12, issue 1, pp. 1 - 19
(Article)
Abstract
Tumor cells may share some patterns of gene expression with their cell of origin, providing clues into the differentiation state and origin of cancer. Here, we study the differentiation state and cellular origin of 1300 childhood and adult kidney tumors. Using single cell mRNA reference maps of normal tissues, we
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quantify reference “cellular signals” in each tumor. Quantifying global differentiation, we find that childhood tumors exhibit fetal cellular signals, replacing the presumption of “fetalness” with a quantitative measure of immaturity. By contrast, in adult cancers our assessment refutes the suggestion of dedifferentiation towards a fetal state in most cases. We find an intimate connection between developmental mesenchymal populations and childhood renal tumors. We demonstrate the diagnostic potential of our approach with a case study of a cryptic renal tumor. Our findings provide a cellular definition of human renal tumors through an approach that is broadly applicable to human cancer.
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Keywords: General Chemistry, General Biochemistry,Genetics and Molecular Biology, General Physics and Astronomy
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: The CUH adult renal cancer sampling had infrastructure support from the Urological Malignancies Programme which is part of the CRUK Cambridge Centre, funded by Cancer Research UK Major Centre Award C9685/A25117, and supported by the NIHR Cambridge BRC. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. F.C.H. acknowledges funding from the ERC advanced grant DynaMech-671174. We thank the Máxima FACS facility for sorting, Single Cell Discoveries for library preparations, and Single Cell Genomics facilities for help with scRNA analysis. J.D. acknowledges funding from the European Research Council (ERC) starting grant 850571, Dutch Cancer Society (KWF/Alpe d’HuZes Bas Mulder Award; KWF/Alpe d’HuZes, #10218), Foundation Children Cancer Free (KiKa #338, L.C.), Oncode Institute. We thank Dr Amos Burke for his contribution. We are grateful to our patients, young and old, for participating in our study. Funding Information: We acknowledge funding from Wellcome (Fellowships to S.B., K.S., J.C.A. 209328/Z/17/ Z, core funding to the Sanger Institute, strategic award 211276/Z/18/Z). Additional support was provided by the St Baldrick’s Foundation (S.B.), Great Ormond Street Hospital Children’s Charity (J.C.A.), Great Ormond Street Hospital Biomedical Research Centre, Olivia Hodson Cancer Fund (K.S.), CRUK (Fellowship to T.J.M.), National Institute for Health Research funded Cambridge Biomedical Research Centre (R.A.B., A.Y.W). The views expressed are those of the authors and not necessarily those of the National Health Service, National Institute for Health Research, or Department of Health. Funding Information: Ethics statement. Human kidney and tumor tissues were collected through studies approved by UK NHS research ethics committees. Patients or guardians provided informed written consent for participation in this study as stipulated by the study protocols. These studies have the following references: NHS National Research Ethics Service reference 03/018 (DIAMOND study; adult kidney tissues); NHS National Research Ethics Service reference 16/EE/0394 (pediatric tissues); NHS National Research Ethics Service reference 96/085 (fetal tissues). Additional fetal tissue was provided by the Joint MRC/Wellcome Trust-funded (grant # 099175/Z/ 12/Z) Human Developmental BiologyResource (HBDR, http://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 UK Human Tissue Authority (HTA;www.hta.gov.uk) and operates in accordance with the relevant HTA Codes of Practice. Fetal tissues from both sources were obtained from terminations and ranged from 7 to 18 post conception weeks (Supplementary Table 1). Organoids were generated from human tissue as approved by the medical ethics committee of the Erasmus Medical Center (Rotterdam, the Netherlands). Publisher Copyright: © 2021, The Author(s).
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