DOI: 10.25345/c5xk85306
title: MassIVE MSV000097266 - Generation of a biliary tract cancer cell line atlas identifies molecular subtypes and therapeutic targets
title: Biliary tract cancers (BTCs) are lethal malignancies, including intrahepatic and extrahepatic cholangiocarcinoma, gallbladder carcinoma, and ampullary carcinoma. Through multi-omics profiling and CRISPR screens of 63 BTC cell lines, we identify widespread EGFR dependency and subtype-specific vulnerabilities with predictive markers. Strategies to overcome targeted therapy resistance include EGFR inhibition potentiating mutant-KRAS and FGFR inhibition, while SHP2 inhibition counters FGFR inhibitor resistance. Clustering by gene/protein expression and dependencies reveals functional subtypes ductal, squamous, and bi-lineage each with distinct survival dependencies. Transcriptional analysis of patient samples highlights the prognostic value of this classification. This BTC cell line atlas uncovers therapeutic targets, defines disease subtypes, and serves as a critical resource for BTC research. Multiplexed proteomics was performed using TMT tags (TMT1 to TMT12) and TMTpro tags (TMT13 to TMT17) and the SPS3 method on an Orbitrap Fusion Lumos instrument. Sample key is as follows: CCLP (ICCL_TMT2:129c, ICCL_TMT6:127n), CCSW1(ICCL_TMT2:128c, ICCL_TMT7:130c), AOVC1 (ICCL_TMT9:129n, ICCL_TMT10:129c), EGI1(ICCL_TMT16:126, ICCL_TMT16:127n), ETK1 (ICCL_TMT16:127c, ICCL_TMT16:128n), G415 (ICCL_TMT11:129c, ICCLTMT12:130n), GB2 (ICCL_TMT1:127n, ICCL_TMT5:128n), HKGZCC (ICCL_TMT4:129n, ICCL_TMT8:128c), HUCCT1 (ICCL_TMT1:127c, ICCL_TMT6:129n), HUH28 (ICCL_TMT4:130n, ICCL_TMT8:128n), GB3 (ICCL_TMT3:131n, ICCL_TMT7:131n), ICC10 (ICCL_TMT1:128c, ICCL_TMT7:126), ICC10-6 (ICCL_TMT4:128n, ICCL_TMT7:127n), ICC10-8 (ICCL_TMT2:131n, ICCL_TMT7:127c), ICC11 (ICCL_TMT4:128c, ICCL_TMT5:129n), ICC12 (ICCL_TMT4:130c, ICCL_TMT6:129c), ICC13-7 (ICCL_TMT2:126, ICCL_TMT8:127c, ICCL_TMT11:129n, ICCL_TMT12:131n), ECC3 (ICCL_TMT1:128n, ICCL_TMT5:127c), ICC16 (ICCL_TMT11:128n, ICCL_TMT12:128c), ICC17 (ICCL_TMT3:129c, ICCL_TMT7:129n), ICC18 (ICCL_TMT13:127c, ICCL_TMT13:128n), ICC19 (ICCL_TMT11:128c, ICCL_TMT12:127c), ICC2 (ICCL_TMT4:127c, ICCL_TMT5:126), ICC20 (ICCL_TMT13:128c, ICCL_TMT13:129n), ICC21 (ICCL_TMT14:131n, ICCL_TMT14:131c), ICC24 (ICCL_TMT13:129c, ICCL_TMT13:130n), ICC25 (ICCL_TMT13:130c, ICCL_TMT13:131n), ICC26 (ICCL_TMT15:128c, ICCL_TMT15:129n), ECC4 (ICCL_TMT4:127n, ICCL_TMT6:131n, ICCL_TMT13:126, ICCL_TMT13:127n), ICC4 (ICCL_TMT9:128n, ICCL_TMT10:130n), ICC5 (ICCL_TMT3:127c, ICCL_TMT6:130n), ICC8 (ICCL_TMT2:127n, ICCL_TMT7:129c), ICC9 (ICCL_TMT2:127c, ICCL_TMT7:128c), KKU100 (ICCL_TMT9:127n, ICCL_TMT10:131n), KKU312 (ICCL_TMT9:129c, ICCL_TMT10:127n), GB4 (ICCL_TMT15:127n, ICCL_TMT15:128n), NOZ (ICCL_TMT16:132c, ICCL_TMT16:133n), OCUG1 (ICCL_TMT16:129n), RBE (ICCL_TMT1:126, ICCL_TMT7:128n), SG231 (ICCL_TMT9:126, ICCL_TMT10:127c), SNU1079 (ICCL_TMT9:130c, ICCL_TMT10:128n), SNU1196 (ICCL_TMT1:130n, ICCL_TMT8:130n), SNU245 (ICCL_TMT17:128n, ICCL_TMT17:129c), SNU308 (ICCL_TMT4:131n, ICCL_TMT8:131n), SNU478 (ICCL_TMT2:128n, ICCL_TMT6:130c), SNU869 (ICCL_TMT4:129c, ICCL_TMT5:130n), SSP25 (ICCL_TMT2:130c, ICCL_TMT5, 131n), TFK1 (ICCL_TMT17:126, ICCL_TMT17:130c) TGC1TKB (ICCL_TMT17:127c, ICCL_TMT17:129n), TGBC52TKB (ICCL_TMT11:130c, ICCL_TMT12:128n), TKKK (ICCL_TMT9:128c, ICCL_TTM10:129n), YSCCC (ICCL_TMT9:127c, ICCL_TMT10:126), ICC7 (ICCL_TMT3:128c, ICCL_TMT5:129c), OZ (ICCL_TMT11:127n, ICCL_TMT12:129n), KMCH1 (ICCL_TMT1:129n, ICCL_TMT8:129c), KKU055 (ICCL_TMT16:131c), ICC28 (ICCL_TMT2:132n, ICCL_TMT3:126), TGBC14TKB (ICCL_TMT11:131n, ICCL_TMT12:130c), PLCPRF5 (ICCL_TMT14:129n, ICCL_TMT14:129c) TONG (ICCL_TMT14:127n, ICCL_TMT14:127c), HUH7 (ICCL_TMT15:129c, ICCL_TMT14:130n, ICCL_TMT14:130c), SNU449 (ICCL_TMT15:131n), SNU387 (ICCL_TMT17:126, ICCL_TMT17:128c), JHH7 (ICCL_TMT15:130n, ICCL_TMT1:130c), SNU475 (ICCL_TMT17:130n, ICCL_TMT17:132n), HEPG2 (ICCL_TMT13:131c, ICCL_TMT13:132n), SNU423 (ICCL_TMT17:131n, ICC_TMT17:131c)