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 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.展开更多
基金supported by a Shared Facility contract from the New York State Department of Health(NYSTEM C029156)Weill Cornell Medicine Department of Surgery,two pilot grants from Center for Advanced Digestive Care and Clinical and Transitional Science Center of Weill Cornell Medical College(to T.E.and S.C.),Alice Bohmfalk Charitable Trust(to F.M.),and National Institutes of Health(R01 CA204228 to S.D.L.).
文摘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.
