A targetable pathway to eliminate TRA-1-60+/TRA-1-81+ chemoresistant cancer cells.

IF 5.3 2区 生物学 Q2 CELL BIOLOGY
Lei Tan, Xiaohua Duan, Pratyusha Mutyala, Ting Zhou, Sadaf Amin, Tuo Zhang, Brian Herbst, Gokce Askan, Tomer Itkin, Zhaoying Xiang, Fabrizio Michelassi, Michael D Lieberman, Christine A Iacobuzio-Donahue, Steven D Leach, Todd Evans, Shuibing Chen
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引用次数: 0

Abstract

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.

消除 TRA-1-60+/TRA-1-81+ 化疗耐药癌细胞的靶向途径。
化疗耐药性是胰腺癌治疗失败的主要原因。识别化疗耐药癌细胞(CCC)中特异表达的细胞表面标志物有助于采用靶向疗法克服化疗耐药性。我们进行了基于抗体的筛选,发现TRA-1-60和TRA-1-81这两种 "干性 "细胞表面标志物在CCC中高度富集。此外,与 TRA-1-60-/TRA-1-81- 细胞相比,TRA-1-60+/TRA-1-81+ 细胞具有化疗抗性。转录组分析发现了 UGT1A10,证明它是维持 TRA-1-60/TRA-1-81 表达和化疗抗性的必要和充分条件。通过高含量化学筛选,我们发现了香豆素,它能下调 UGT1A10,消除 TRA-1-60/TRA-1-81 的表达,并增加体外和体内的化疗敏感性。最后,TRA-1-60/TRA-1-81 在原发性癌症组织中的表达具有高度特异性,并与化疗耐药性和生存期短呈正相关,这凸显了它们在靶向治疗中的潜力。因此,我们发现了一种受促进化疗耐药性途径调控的新型 CCC 表面标记物,以及一种靶向该途径的主要候选药物。
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来源期刊
CiteScore
9.60
自引率
1.80%
发文量
1383
期刊介绍: The Journal of Molecular Cell Biology ( JMCB ) is a full open access, peer-reviewed online journal interested in inter-disciplinary studies at the cross-sections between molecular and cell biology as well as other disciplines of life sciences. The broad scope of JMCB reflects the merging of these life science disciplines such as stem cell research, signaling, genetics, epigenetics, genomics, development, immunology, cancer biology, molecular pathogenesis, neuroscience, and systems biology. The journal will publish primary research papers with findings of unusual significance and broad scientific interest. Review articles, letters and commentary on timely issues are also welcome. JMCB features an outstanding Editorial Board, which will serve as scientific advisors to the journal and provide strategic guidance for the development of the journal. By selecting only the best papers for publication, JMCB will provide a first rate publishing forum for scientists all over the world.
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