Single-cell trajectory analysis reveals a CD9 positive state to contribute to exit from stem cell-like and embryonic diapause states and transit to drug-resistant states.
Single-cell trajectory analysis reveals a CD9 positive state to contribute to exit from stem cell-like and embryonic diapause states and transit to drug-resistant states.
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DOI：
10.1038/s41420-023-01586-9
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发表时间：
2023-08-04
影响因子：
7
通讯作者：
Mills, Gordon B.
中科院分区：
文献类型：
--
作者：
Li, Xi;Poire, Alfonso;Jeong, Kang Jin;Zhang, Dong;Chen, Gang;Sun, Chaoyang;Mills, Gordon B.
溴和末端外结构域（BET）抑制剂（BETi）已在临床前模型和临床试验中显示出减少肿瘤生长。然而，毒性和快速出现的耐药性限制了它们的临床应用。为了鉴定获得对JQ1 BETi的抗性的潜在状态变化，我们重新分析了来自JQ1敏感和抗性SUM149和SUM159三阴性乳腺癌细胞系的单细胞RNAseq数据。亲本和JQ1抗性的SUM149和SUM159表现出干细胞样和胚胎滞育（SCLED）细胞状态以及SCLED状态之间的过渡细胞状态，其存在于未经处理的细胞和JQ1处理的细胞中，以及许多JQ1抗性细胞状态。过渡细胞状态转录特征而非SCLED状态转录特征预测基底样乳腺癌患者的预后恶化，表明从SCLED状态到耐药状态的转变有助于患者预后。SUM149和SUM159进入移行细胞状态的特征在于CD9四跨膜蛋白的表达升高。在体外敲低或抑制CD9致敏细胞对多种靶向和细胞毒性药物的反应。重要的是，CD9敲低或阻断通过将细胞捕获在SCLED状态并限制转运至抗性细胞状态而在体内使SUM149对JQ1敏感。因此，CD9对于从SCLED状态转变为治疗抗性细胞状态似乎是关键的，并且值得探索作为基底样乳腺癌的治疗靶点。
Bromo- and extra-terminal domain (BET) inhibitors (BETi) have been shown to decrease tumor growth in preclinical models and clinical trials. However, toxicity and rapid emergence of resistance have limited their clinical implementation. To identify state changes underlying acquisition of resistance to the JQ1 BETi, we reanalyzed single-cell RNAseq data from JQ1 sensitive and resistant SUM149 and SUM159 triple-negative breast cancer cell lines. Parental and JQ1-resistant SUM149 and SUM159 exhibited a stem cell-like and embryonic diapause (SCLED) cell state as well as a transitional cell state between the SCLED state that is present in both treatment naïve and JQ1 treated cells, and a number of JQ1 resistant cell states. A transitional cell state transcriptional signature but not a SCLED state transcriptional signature predicted worsened outcomes in basal-like breast cancer patients suggesting that transit from the SCLED state to drug-resistant states contributes to patient outcomes. Entry of SUM149 and SUM159 into the transitional cell state was characterized by elevated expression of the CD9 tetraspanin. Knockdown or inhibition of CD9-sensitized cells to multiple targeted and cytotoxic drugs in vitro. Importantly, CD9 knockdown or blockade sensitized SUM149 to JQ1 in vivo by trapping cells in the SCLED state and limiting transit to resistant cell states. Thus, CD9 appears to be critical for the transition from a SCLED state into treatment-resistant cell states and warrants exploration as a therapeutic target in basal-like breast cancer.
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DOI：
10.1093/jnci/djt376
发表时间：
2014-02
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Liu NQ;Stingl C;Look MP;Smid M;Braakman RB;De Marchi T;Sieuwerts AM;Span PN;Sweep FC;Linderholm BK;Mangia A;Paradiso A;Dirix LY;Van Laere SJ;Luider TM;Martens JW;Foekens JA;Umar A
通讯作者：
Umar A
关于癌症基因组地图集的泛伴奏蛋白质组学观点。
影响因子：
16.6
作者：
Akbani, Rehan;Ng, Patrick Kwok Shing;Werner, Henrica M. J.;Shahmoradgoli, Maria;Zhang, Fan;Ju, Zhenlin;Liu, Wenbin;Yang, Ji-Yeon;Yoshihara, Kosuke;Li, Jun;Ling, Shiyun;Seviour, Elena G.;Ram, Prahlad T.;Minna, John D.;Diao, Lixia;Tong, Pan;Heymach, John V.;Hill, Steven M.;Dondelinger, Frank;Stadler, Nicolas;Byers, Lauren A.;Meric-Bernstam, Funda;Weinstein, John N.;Broom, Bradley M.;Verhaak, Roeland G. W.;Liang, Han;Mukherjee, Sach;Lu, Yiling;Mills, Gordon B.
通讯作者：
Mills, Gordon B.
影响因子：
16.6
作者：
Karaayvaz M;Cristea S;Gillespie SM;Patel AP;Mylvaganam R;Luo CC;Specht MC;Bernstein BE;Michor F;Ellisen LW
通讯作者：
Ellisen LW
影响因子：
168.9
作者：
Denkert, Carsten;Liedtke, Cornelia;von Minckwitz, Gunter
通讯作者：
von Minckwitz, Gunter
影响因子：
3.7
作者：
Gustafson-Wagner E;Stipp CS
通讯作者：
Stipp CS