老靶点可使三阴性乳腺癌改邪归正
癌细胞通过促进核苷酸代谢，可以帮助其失去分化作用而疯狂繁殖，但是核苷酸代谢增强对于肿瘤去分化的影响机制尚不明确。
2019年2月8日，英国《自然》旗下《细胞死亡与分化》在线发表德国埃尔朗根纽伦堡大学、法兰克福肿瘤生物学实验治疗研究院、美国宾夕法尼亚大学、埃默里大学、南卡罗来纳大学、土耳其毕尔肯大学、荷兰癌症研究院、意大利都灵大学、韩国庆熙大学、新加坡国立大学的研究报告，发现一种核苷酸代谢酶和已知药物靶点——胸苷酸合成酶对于乳腺癌细胞去分化的作用及临床意义。
体外研究发现，抑制胸苷酸合成酶基因表达后，CD24阳性分化细胞数量增加，肿瘤细胞的转移能力和成球能力减弱。RNA测序特征分析表明，抑制胸苷酸合成酶基因表达后，可以阻遏上皮→间质转化相关基因。机制分析发现，通过促进依赖二氢嘧啶脱氢酶的嘧啶分解代谢，胸苷酸合成酶酶活性对于癌细胞维持上皮→间质转化和干细胞样状态是必需的。此外，该研究还发现低分化和三阴性乳腺癌患者组织的胸苷酸合成酶水平显著较高，并且与预后较差密切相关。
因此，该研究为深入阐明核苷酸代谢对增殖和分化的作用提供了基础，并且为设计乳腺癌治疗新药联合提供了方法。
Cell Death Differ. 2019 Feb 8. [Epub ahead of print]
Thymidylate synthase maintains the de-differentiated state of triple negative breast cancers.
Aarif Siddiqui, Paradesi Naidu Gollavilli, Annemarie Schwab, Maria Eleni Vazakidou, Pelin G. Ersan, Mallika Ramakrishnan, Dick Pluim, Si'Ana Coggins, Ozge Saatci, Laura Annaratone, Jan HM Schellens, Baek Kim, Irfan Ahmed Asangani, Suhail Ahmed Kabeer Rasheed, Caterina Marchiò, Ozgur Sahin, Paolo Ceppi.
FAU Erlangen-Nürnberg, Erlangen, Germany; University of Pennsylvania, Philadelphia, PA, USA; Bilkent University, Ankara, Turkey; Georg-Speyer-Haus Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany; Netherland Cancer Institute, Amsterdam, The Netherlands; Emory University School of Medicine, Atlanta, GA, USA; University of South Carolina, Columbia, SC, USA; University of Turin, Turin, Italy; Kyung Hee University, Seoul, South Korea; Duke-NUS Medical School, Singapore, Singapore; Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.
Cancer cells frequently boost nucleotide metabolism (NM) to support their increased proliferation, but the consequences of elevated NM on tumor de-differentiation are mostly unexplored. Here, we identified a role for thymidylate synthase (TS), a NM enzyme and established drug target, in cancer cell de-differentiation and investigated its clinical significance in breast cancer (BC). In vitro, TS knockdown increased the population of CD24+ differentiated cells, and attenuated migration and sphere-formation. RNA-seq profiling indicated repression of epithelial-to-mesenchymal transition (EMT) signature genes upon TS knockdown, and TS-deficient cells showed an increased ability to invade and metastasize in vivo, consistent with the occurrence of a partial EMT phenotype. Mechanistically, TS enzymatic activity was found essential for maintenance of the EMT/stem-like state by fueling a dihydropyrimidine dehydrogenase—dependent pyrimidine catabolism. In patient tissues, TS levels were found significantly higher in poorly differentiated and in triple negative BC, and strongly correlated with worse prognosis. The present study provides the rationale to study in-depth the role of NM at the crossroads of proliferation and differentiation, and depicts new avenues for the design of novel drug combinations for the treatment of BC.
DOI: 10.1038/s41418-019-0289-6
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