A Targetable Pathway to Eliminate TRA-1-60+/TRA-1-81+ Chemoresistant Cancer Cells.

TitleA Targetable Pathway to Eliminate TRA-1-60+/TRA-1-81+ Chemoresistant Cancer Cells.
Publication TypeJournal Article
Year of Publication2023
AuthorsTan L, Duan X, Mutyala P, Zhou T, Amin S, Zhang T, Herbst B, Askan G, Itkin T, Xiang Z, Michelassi F, Lieberman MD, Iacobuzio-Donahue CA, Leach SD, Evans T, Chen S
JournalJ Mol Cell Biol
Date Published2023 Jun 16

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.

Alternate JournalJ Mol Cell Biol
PubMed ID37327088