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

  • J Mol Cell Biol. 2023 Nov 27;15(6):mjad039. doi: 10.1093/jmcb/mjad039.
Lei Tan  1  2 ,  Xiaohua Duan  1  3 ,  Pratyusha Mutyala  1 ,  Ting Zhou  4 ,  Sadaf Amin  1 ,  Tuo Zhang  5 ,  Brian Herbst  6 ,  Gokce Askan  6 ,  Tomer Itkin  7 ,  Zhaoying Xiang  5 ,  Fabrizio Michelassi  1 ,  Michael D Lieberman  1 ,  Christine A Iacobuzio-Donahue  6 ,  Steven D Leach  8 ,  Todd Evans  1  3 ,  Shuibing Chen  1  3
Affiliations
  • 1. Department of Surgery, Weill Cornell Medicine, New York, NY 10065, USA.
  • 2. Center for Energy Metabolism and Reproduction, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
  • 3. Center for Genomic Health, Weill Cornell Medicine, New York, NY 10065, USA.
  • 4. The 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.
  • 5. Genomic Resource Core Facility, Weill Cornell Medical College, New York, NY 10065, USA.
  • 6. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 7. Division of Regenerative Medicine, Hartman Institute for Therapeutic Organ Regeneration, Ansary Stem Cell Institute, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
  • 8. Dartmouth Cancer Center, Darmouth College, Hanover, NH 03755, USA.
PMID: 37327088 DOI: 10.1093/jmcb/mjad039
Abstract

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.

Keywords
Cymarin; TRA-1-60/TRA-1-81; UGT1A10; chemoresistance; pancreatic cancer.
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