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A targetable pathway to eliminate TRA-1-60+/TRA-1-81+ chemoresistant cancer cells
Lei Tan1,2,† , Xiaohua Duan1,3,† , Pratyusha Mutyala1 , Ting Zhou4 , Sadaf Amin1 , Tuo Zhang5 , Brian Herbst6 , Gokce Askan6 , Tomer Itkin7 , Zhaoying Xiang5 , Fabrizio Michelassi1 , Michael D. Lieberman1 , Christine A. Iacobuzio-Donahue6 , Steven D. Leach8 , Todd Evans1,3,* , Shuibing Chen1,3,*
1Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA
2Center for Energy Metabolism and Reproduction, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
3Center for Genomic Health, Weill Cornell Medicine, New York, NY 10065, USA
4The SKI Stem Cell Research Facility, The Center for Stem Cell Biology and Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
5Genomic Resource Core Facility, Weill Cornell Medical College, New York, NY 10065, USA
6Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
7Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
8Dartmouth Cancer Center, Darmouth College, Hanover, NH 03755, USA
These authors contributed equally to this work.
*Correspondence to:Shuibing Chen , Todd Evans ,
J Mol Cell Biol, Volume 15, Issue 6, June 2023, mjad039,
Keyword: pancreatic cancer, TRA-1-60/TRA-1-81, chemoresistance, UGT1A10, Cymarin

Chemoresistance is a primary cause of treatment failure in pancreatic cancer. Identifying cell surface markers specifically expressed in chemoresistant cancer cells (CCCs) could facilitate targeted therapies to overcome chemoresistance. We performed an antibody-based screen and found that TRA-1-60 and TRA-1-81, two ‘stemness’ cell surface markers, are highly enriched in CCCs. Furthermore, TRA-1-60+/TRA-1-81+ cells are chemoresistant compared to TRA-1-60/TRA-1-81 cells. Transcriptome profiling identified UGT1A10, shown to be both necessary and sufficient to maintain TRA-1-60/TRA-1-81 expression and chemoresistance. From 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 vivo. Finally, 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 therapy. Therefore, 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.