Generation and multi-dimensional profiling of a childhood cancer cell line atlas defines new therapeutic opportunities

Claire Xin Sun; Paul Daniel; Gabrielle Bradshaw; Hui Shi; Melissa Loi; Nicole Chew; Sarah Parackal; Vanessa Tsui; Yuqing Liang; Mateusz Koptyra; Shazia Adjumain; Christie Sun; Wai Chin Chong; Dasun Fernando; Caroline Drinkwater; Motahhareh Tourchi; Dilru Habarakada; Dhanya Sooraj; Diana Carvalho; Phillip B Storm; Valerie Baubet; Leanne C Sayles; Elisabet Fernandez; Thy Nguyen; Mia Pörksen; Anh Doan; Duncan E Crombie; Monty Panday; Nataliya Zhukova; Matthew D Dun; Louise E Ludlow; Bryan Day; Brett W Stringer; Naama Neeman; Jeffrey A Rubens; Eric H Raabe; Maria Vinci; Vanessa Tyrrell; Jamie I Fletcher; Paul G Ekert; Biljana Dumevska; David S Ziegler; Maria Tsoli; Nur Farhana Syed Sulaiman; Amos Hong Pheng Loh; Sharon Yin Yee Low; E Alejandro Sweet-Cordero; Michelle Monje; Adam Resnick; Chris Jones; Peter Downie; Bryan Williams; Joseph Rosenbluh; Daniel Gough; Jason E Cain; Ron Firestein

doi:10.1016/j.ccell.2023.03.007

Generation and multi-dimensional profiling of a childhood cancer cell line atlas defines new therapeutic opportunities

Cancer Cell. 2023 Apr 10;41(4):660-677.e7. doi: 10.1016/j.ccell.2023.03.007. Epub 2023 Mar 30.

Authors

Claire Xin Sun¹, Paul Daniel¹, Gabrielle Bradshaw¹, Hui Shi¹, Melissa Loi¹, Nicole Chew¹, Sarah Parackal¹, Vanessa Tsui¹, Yuqing Liang¹, Mateusz Koptyra², Shazia Adjumain¹, Christie Sun¹, Wai Chin Chong¹, Dasun Fernando¹, Caroline Drinkwater¹, Motahhareh Tourchi¹, Dilru Habarakada¹, Dhanya Sooraj¹, Diana Carvalho³, Phillip B Storm², Valerie Baubet², Leanne C Sayles⁴, Elisabet Fernandez³, Thy Nguyen¹, Mia Pörksen⁵, Anh Doan¹, Duncan E Crombie¹, Monty Panday¹, Nataliya Zhukova⁶, Matthew D Dun⁷, Louise E Ludlow⁸, Bryan Day⁹, Brett W Stringer⁹, Naama Neeman¹, Jeffrey A Rubens¹⁰, Eric H Raabe¹¹, Maria Vinci¹², Vanessa Tyrrell¹³, Jamie I Fletcher¹³, Paul G Ekert¹⁴, Biljana Dumevska¹⁵, David S Ziegler¹⁶, Maria Tsoli¹³, Nur Farhana Syed Sulaiman¹⁷, Amos Hong Pheng Loh¹⁸, Sharon Yin Yee Low¹⁹, E Alejandro Sweet-Cordero⁴, Michelle Monje²⁰, Adam Resnick², Chris Jones³, Peter Downie²¹, Bryan Williams¹, Joseph Rosenbluh²², Daniel Gough¹, Jason E Cain¹, Ron Firestein²³

Affiliations

¹ Centre for Cancer Research, Hudson Institute of Medical Research, Monash University, Clayton, VIC 3168, Australia; Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3168, Australia.
² Center for Data Driven Discovery in Biomedicine, Neurosurgery Department, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
³ Division of Molecular Pathology, The Institute of Cancer Research, London SM2 5NG, UK; Division of Cancer Therapeutics, The Institute of Cancer Research, London SM2 5NG, UK.
⁴ Department of Pediatrics, University of California San Francisco, San Francisco, CA 94158, USA.
⁵ Centre for Cancer Research, Hudson Institute of Medical Research, Monash University, Clayton, VIC 3168, Australia; Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3168, Australia; Department of Paediatrics, University of Lübeck, 23562 Lübeck, Germany.
⁶ Centre for Cancer Research, Hudson Institute of Medical Research, Monash University, Clayton, VIC 3168, Australia; Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3168, Australia; Children's Cancer Centre, Monash Children's Hospital, Monash Health, Clayton, VIC 3168, Australia; Department of Paediatrics, Monash University, Clayton, VIC 3168, Australia.
⁷ Hunter Cancer Research Alliance, University of Newcastle, Callaghan, NSW 2308, Australia; School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia.
⁸ Children's Cancer Centre Biobank, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.
⁹ QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.
¹⁰ Division of Pediatric Oncology, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹¹ Division of Pediatric Oncology, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹² Department of Onco-haematology, Cell and Gene Therapy, Bambino Gesù Children's Hospital-IRCCS, 00165 Rome, Italy.
¹³ Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia.
¹⁴ Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia; Centre for Cancer Immunotherapy, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Department of Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.
¹⁵ Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.
¹⁶ Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia; Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW 2031, Australia.
¹⁷ Neurosurgical Service, KK Women's and Children's Hospital, Singapore 229899, Singapore; VIVA-KKH Paediatric Brain and Solid Tumours Programme, Singapore 229899, Singapore.
¹⁸ VIVA-KKH Paediatric Brain and Solid Tumours Programme, Singapore 229899, Singapore; Duke-NUS Medical School, Singapore 169857, Singapore.
¹⁹ Neurosurgical Service, KK Women's and Children's Hospital, Singapore 229899, Singapore; VIVA-KKH Paediatric Brain and Solid Tumours Programme, Singapore 229899, Singapore; SingHealth-Duke NUS Neuroscience Academic Clinical Programme, Singapore 308433, Singapore; SingHealth-Duke NUS Paediatrics Academic Clinical Programme, Singapore 229899, Singapore.
²⁰ Department of Neurology, Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
²¹ Children's Cancer Centre, Monash Children's Hospital, Monash Health, Clayton, VIC 3168, Australia; Department of Paediatrics, Monash University, Clayton, VIC 3168, Australia.
²² Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3168, Australia.
²³ Centre for Cancer Research, Hudson Institute of Medical Research, Monash University, Clayton, VIC 3168, Australia; Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3168, Australia. Electronic address: [email protected].

PMID: 37001527
DOI: 10.1016/j.ccell.2023.03.007

Abstract

Pediatric solid and central nervous system tumors are the leading cause of cancer-related death among children. Identifying new targeted therapies necessitates the use of pediatric cancer models that faithfully recapitulate the patient's disease. However, the generation and characterization of pediatric cancer models has significantly lagged behind adult cancers, underscoring the urgent need to develop pediatric-focused cell line resources. Herein, we establish a single-site collection of 261 cell lines, including 224 pediatric cell lines representing 18 distinct extracranial and brain childhood tumor types. We subjected 182 cell lines to multi-omics analyses (DNA sequencing, RNA sequencing, DNA methylation), and in parallel performed pharmacological and genetic CRISPR-Cas9 loss-of-function screens to identify pediatric-specific treatment opportunities and biomarkers. Our work provides insight into specific pathway vulnerabilities in molecularly defined pediatric tumor classes and uncovers biomarker-linked therapeutic opportunities of clinical relevance. Cell line data and resources are provided in an open access portal.

Keywords: CRISPR screens; biomarker; brain cancer; cell line atlas; epigenetics; machine learning; multi-omics feature analysis; pediatric cancers; precision medicine; targeted therapy.

Generation and multi-dimensional profiling of a childhood cancer cell line atlas defines new therapeutic opportunities

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