Hartman Institute for Therapeutic Organ Regeneration

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
Volume15
Issue6
Date Published2023 Nov 27
ISSN1759-4685
KeywordsCell 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>

DOI10.1093/jmcb/mjad039
Alternate JournalJ Mol Cell Biol
PubMed ID37327088
PubMed Central IDPMC10847630
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
R01 CA204228 / CA / NCI NIH HHS / United States
R01 CA204228 / NH / NIH HHS / United States

Weill Cornell Medicine
Hartman Institute for Therapeutic Organ Regeneration
1300 York Ave, Box 136 New York, NY 10065