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

Lei Tan, Xiaohua Duan, Pratyusha Mutyala, Ting Zhou, Sadaf Amin, Brian Herbst, Gokce Askan, Tomer Itkin, Zhaoying Xiang, Fabrizio Michelassi, Michael D. Lieberman, Christine A. Iacobuzio-Donahue, Steven D. Leach, Todd Evans, Shuibing Chen

Research output: Contribution to journalArticlepeer-review

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. Further- more, 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.

Original languageEnglish
Article numbermjad039
JournalJournal of Molecular Cell Biology
Volume15
Issue number6
DOIs
StatePublished - 1 Jun 2023
Externally publishedYes

Keywords

  • Cymarin
  • TRA-1-60/TRA-1-81
  • UGT1A10
  • chemoresistance
  • pancreatic cancer

All Science Journal Classification (ASJC) codes

  • General Medicine

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