TY - JOUR
T1 - A targetable pathway to eliminate TRA-1-60+ /TRA-1-81+ chemoresistant cancer cells
AU - Tan, Lei
AU - Duan, Xiaohua
AU - Mutyala, Pratyusha
AU - Zhou, Ting
AU - Amin, Sadaf
AU - Zhang, Tuo
AU - Herbst, Brian
AU - Askan, Gokce
AU - Itkin, Tomer
AU - Xiang, Zhaoying
AU - Michelassi, Fabrizio
AU - Lieberman, Michael D.
AU - Iacobuzio-Donahue, Christine A.
AU - Leach, Steven D.
AU - Evans, Todd
AU - Chen, Shuibing
N1 - Publisher Copyright:
© The Author(s) (2023).
PY - 2023/6/1
Y1 - 2023/6/1
N2 - 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.
AB - 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.
KW - Cymarin
KW - TRA-1-60/TRA-1-81
KW - UGT1A10
KW - chemoresistance
KW - pancreatic cancer
UR - http://www.scopus.com/inward/record.url?scp=85184516449&partnerID=8YFLogxK
U2 - 10.1093/jmcb/mjad039
DO - 10.1093/jmcb/mjad039
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C2 - 37327088
AN - SCOPUS:85184516449
SN - 1674-2788
VL - 15
JO - Journal of Molecular Cell Biology
JF - Journal of Molecular Cell Biology
IS - 6
M1 - mjad039
ER -
