Epigenetic targeting of neuropilin-1 prevents bypass signaling in drug-resistant breast cancer.
Epigenetic targeting of neuropilin-1 prevents bypass signaling in drug-resistant breast cancer.
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DOI：
10.1038/s41388-020-01530-6
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发表时间：
2021-01
期刊：
影响因子：
8
通讯作者：
Wendt MK
中科院分区：
文献类型：
--
作者：
Abdullah A;Akhand SS;Paez JSP;Brown W;Pan L;Libring S;Badamy M;Dykuizen E;Solorio L;Andy Tao W;Wendt MK
使用靶向抗体和激酶抑制剂治疗人表皮生长因子受体2（HER 2）扩增的乳腺癌，但对这些疗法的耐药性导致转移性疾病的全身性肿瘤复发。在此，我们进行了基因表达分析的HER 2激酶受体耐药细胞系相比，他们的药物敏感的同行。这些数据证明了上皮-间质转化（EMT）的诱导，其包括成纤维细胞生长因子受体1（FGFR 1）和称为神经纤毛蛋白（NRP）的轴突引导分子的表达增强。FGFR 1的免疫沉淀结合质谱表明，FGFR 1与NRP形成物理复合物，其在诱导EMT时增强。共聚焦成像显示FGFR 1和NRP 1主要在整个细胞质中相互作用。沿着这些路线，短发夹RNA介导的NRP 1消耗，但不使用NRP 1阻断抗体，抑制FGFR信号传导，并减少肿瘤细胞生长在体外和体内。我们的研究结果进一步表明，NRP 1上调EMT期间介导的染色质阅读器蛋白，溴结构域4（BRD 4）在NRP 1近端启动子区的结合。BRD 4的药理学抑制降低了NRP 1表达并消除了FGF介导的肿瘤细胞生长。总之，我们的研究表明，NRPs促进异常的生长因子信号在EMT相关的耐药性和转移。表观遗传调节剂与FGFR靶向激酶抑制剂的药理学组合可为患有耐药转移性疾病的乳腺癌患者提供改善的结局。
Human epidermal growth factor receptor 2 (HER2)-amplified breast cancers are treated using targeted antibodies and kinase inhibitors, but resistance to these therapies leads to systemic tumor recurrence of metastatic disease. Herein, we conducted gene expression analyses of HER2 kinase inhibitor-resistant cell lines as compared to their drug-sensitive counterparts. These data demonstrate the induction of epithelial–mesenchymal transition (EMT), which included enhanced expression of fibroblast growth factor receptor 1 (FGFR1) and axonal guidance molecules known as neuropilins (NRPs). Immunoprecipitation of FGFR1 coupled with mass spectroscopy indicated that FGFR1 forms a physical complex with NRPs, which is enhanced upon induction of EMT. Confocal imaging revealed that FGFR1 and NRP1 predominantly interact throughout the cytoplasm. Along these lines, short hairpin RNA-mediated depletion of NRP1, but not the use of NRP1-blocking antibodies, inhibited FGFR signaling and reduced tumor cell growth in vitro and in vivo. Our results further indicate that NRP1 upregulation during EMT is mediated via binding of the chromatin reader protein, bromodomain containing 4 (BRD4) in the NRP1 proximal promoter region. Pharmacological inhibition of BRD4 decreased NRP1 expression and ablated FGF-mediated tumor cell growth. Overall, our studies indicate that NRPs facilitate aberrant growth factor signaling during EMT-associated drug resistance and metastasis. Pharmacological combination of epigenetic modulators with FGFR-targeted kinase inhibitors may provide improved outcomes for breast cancer patients with drug-resistant metastatic disease.
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影响因子：
21.3
作者：
Er EE;Valiente M;Ganesh K;Zou Y;Agrawal S;Hu J;Griscom B;Rosenblum M;Boire A;Brogi E;Giancotti FG;Schachner M;Malladi S;Massagué J
通讯作者：
Massagué J
影响因子：
11
作者：
Lee TW;Lee TI;Lin YK;Kao YH;Chen YJ
通讯作者：
Chen YJ
影响因子：
11.2
作者：
Dey, Julien H.;Bianchi, Fabrizio;Hynes, Nancy E.
通讯作者：
Hynes, Nancy E.
影响因子：
7.3
作者：
Bumbaca, Daniela;Xiang, Hong;Shen, Ben-Quan
通讯作者：
Shen, Ben-Quan
影响因子：
11.1
作者：
Chua, Vivian;Orloff, Marlana;Aplin, Andrew E.
通讯作者：
Aplin, Andrew E.