Title | A targetable pathway to eliminate TRA-1-60+/TRA-1-81+ chemoresistant cancer cells. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Tan 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 |
Journal | J Mol Cell Biol |
Volume | 15 |
Issue | 6 |
Date Published | 2023 Nov 27 |
ISSN | 1759-4685 |
Keywords | Cell Line, Tumor, Drug Resistance, Neoplasm, Gene Expression Profiling, Humans, Pancreatic Neoplasms |
Abstract | <p>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.</p> |
DOI | 10.1093/jmcb/mjad039 |
Alternate Journal | J Mol Cell Biol |
PubMed ID | 37327088 |
PubMed Central ID | PMC10847630 |
Grant List | P30 CA008748 / CA / NCI NIH HHS / United States R01 CA204228 / CA / NCI NIH HHS / United States R01 CA204228 / NH / NIH HHS / United States |