儿童癌细胞系图谱的生成与多维分析确定了新的治疗机会。

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

作者信息

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

机构信息

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.

Center for Data Driven Discovery in Biomedicine, Neurosurgery Department, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

出版信息

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

DOI:10.1016/j.ccell.2023.03.007

PMID:37001527

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.

摘要

小儿实体瘤和中枢神经系统肿瘤是儿童癌症相关死亡的主要原因。确定新的靶向治疗方法需要使用能够忠实地重现患者疾病的小儿癌症模型。然而，小儿癌症模型的生成和特征描述明显落后于成人癌症，这凸显了开发以小儿为重点的细胞系资源的迫切需求。在此，我们建立了一个包含261个细胞系的单站点集合，其中包括224个小儿细胞系，代表18种不同的颅外和脑儿童肿瘤类型。我们对182个细胞系进行了多组学分析（DNA测序、RNA测序、DNA甲基化），并同时进行了药理学和基因CRISPR-Cas9功能丧失筛选，以确定小儿特异性治疗机会和生物标志物。我们的工作深入了解了分子定义的小儿肿瘤类别中的特定途径脆弱性，并揭示了具有临床相关性的生物标志物相关治疗机会。细胞系数据和资源在一个开放获取的门户网站上提供。