Author:
Vijay Vindhya,Karisani Negin,Shi Lei,Hung Yu-Han,Vu Phuong,Kattel Prabhat,Kenney Lauren,Merritt Joshua,Adil Ramzi,Wu Qibiao,Zhen Yuanli,Morris Robert,Kreuzer Johannes,Kathiresan Meena,Herrera Lopez Xcanda Ixchel,Ellis Haley,Gritti Ilaria,Lecorgne Lilian,Farag Ines,Popa Alexandra,Shen William,Kato Hiroyuki,Xu Qin,Balasooriya Eranga R.,Wu Meng-Ju,Chaturantabut Saireudee,Kelley Robin K.,Cleary James M.,Lawrence Michael S.,Root David,Benes Cyril H.,Deshpande Vikram,Juric Dejan,Sellers William R.,Ferrone Cristina R.,Haas Wilhelm,Vazquez Francisca,Getz Gad,Bardeesy Nabeel
Abstract
AbstractBiliary tract cancers (BTCs) are a group of deadly malignancies encompassing intrahepatic and extrahepatic cholangiocarcinoma, gallbladder carcinoma, and ampullary carcinoma. Here, we present the integrative analysis of 63 BTC cell lines via multi-omics clustering and genome- scale CRISPR screens, providing a platform to illuminate BTC biology and inform therapeutic development. We identify dependencies broadly enriched in BTC compared to other cancers as well as dependencies selective to the anatomic subtypes. Notably, cholangiocarcinoma cell lines are stratified into distinct lineage subtypes based on biliary or dual biliary/hepatocyte marker signatures, associated with dependency on specific lineage survival factors. Transcriptional analysis of patient specimens demonstrates the prognostic significance of these lineage subtypes. Additionally, we delineate strategies to enhance targeted therapies or to overcome resistance in cell lines with key driver gene mutations. Furthermore, clustering based on dependencies and proteomics data elucidates unexpected functional relationships, including a BTC subgroup with partial squamous differentiation. Thus, this cell line atlas reveals potential therapeutic targets in molecularly defined BTCs, unveils biologically distinct disease subtypes, and offers a vital resource for BTC research.
Publisher
Cold Spring Harbor Laboratory