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A targetable pathway to eliminate TRA-1-60^(+)/TRA-1-81^(+)chemoresistant cancer cells

Journal of Molecular Cell Biology 2023年第6期15卷 25-39页

作者： Lei Tan Xiaohua Duan pratyusha mutyala Ting Zhou Sadaf Amin Tuo Zhang Brian Herbst Gokce Askan Tomer Itkin Zhaoying Xiang Fabrizio Michelassi Michael D.Lieberman Christine AIacobuzio-Donahue Steven DLeach Todd Evans Shuibing Chen Department of Surgery Weill Cornell MedicineNew YorkNY 10065USA Center for Energy Metabolism and Reproduction Institute of Biomedicine and BiotechnologyShenzhen Institute of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China Center for Genomic Health Weill Cornell MedicineNew YorkNY 10065USA The SKI Stem Cell Research Facility The Center for Stem Cell Biology and Developmental Biology ProgramMemorial Sloan Kettering Cancer CenterNew YorkNY 10065USA Genomic Resource Core Facility Weill Cornell Medical CollegeNew YorkNY 10065USA Rubenstein Center for Pancreatic Cancer Research Memorial Sloan Kettering Cancer CenterNew YorkNY 10065USA Division of Regenerative Medicine Hartman Institute for Therapeutic Organ RegenerationAnsary Stem Cell InstituteDepartment of MedicineWeill Cornell MedicineNew YorkNY 10065USA Dartmouth Cancer Center Darmouth CollegeHanoverNH 03755USA

Chemoresistance is a primary cause of treatment failure in pancreatic *** cell surface markers specifically expressed in chemoresistant cancer cells(CCCs)could facilitate targeted therapies to overcome *** performed an antibody-based screen and found that TRA-1-60 and TRA-1-81,two‘stemness’cell surface markers,are highly enriched in ***-more,TRA-1-60^(+)/TRA-1-81^(+)cells are chemoresistant compared to TRA-1-60^(-)/TRA-1-81^(-)*** profiling identified UGT1A10,shown to be both necessary and sufficient to maintain TRA-1-60/TRA-1-81 expression and *** a high-content chemical screen,we identified Cymarin,which downregulates UGT1A10,eliminates TRA-1-60/TRA-1-81 expression,and increases chemosensitivity both in vitro and in ***,TRA-1-60/TRA-1-81 expression is highly specific in primary cancer tissue and positively correlated with chemoresistance and short survival,which highlights their potentiality for targeted ***,we discovered a novel CCC surface marker regulated by a pathway that promotes chemoresistance,as well as a leading drug candidate to target this pathway.

关键词： pancreatic cancer TRA-1-60/TRA-1-81 chemoresistance UGT1A10 Cymarin

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