Alternative splice variants of DCLK1 mark cancer stem cells, promote self-renewal and drug-resistance, and can be targeted to inhibit tumorigenesis in kidney cancer.
Alternative splice variants of DCLK1 mark cancer stem cells, promote self-renewal and drug-resistance, and can be targeted to inhibit tumorigenesis in kidney cancer.
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DOI：
10.1002/ijc.31400
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发表时间：
2018-09-01
影响因子：
6.4
通讯作者：
Houchen CW
中科院分区：
文献类型：
--
作者：
Ge Y;Weygant N;Qu D;May R;Berry WL;Yao J;Chandrakesan P;Zheng W;Zhao L;Zhao KL;Drake M;Vega KJ;Bronze MS;Tomasek JJ;An G;Houchen CW
肾细胞癌（RCC）是一种常见的破坏性疾病，其特征在于缺氧微环境、上皮-间质转化和对治疗的强抗性，这证明了癌症干细胞（CSC）的存在。各种CSC标志物已在RCC中进行了研究，但总体而言，关于其作用的数据有限，并且大多数研究的标志物相对非特异性。双皮质素样激酶1（DCLK 1）是胃肠道中经验证的CSC标志物，在其他癌症中具有同等作用的证据正在积累。我们使用生物信息学，免疫组织化学，流式细胞术，球体自我更新和化疗耐药分析，结合过表达和siRNA敲低，研究干细胞支持作用的DCLK 1选择性剪接变异体（DCLK 1 ASVs）在肾细胞癌。为了直接靶向表达DCLK 1 ASV的肿瘤细胞，我们开发了一种新型单克隆抗体（CBT-15），并将其全身递送至RCC肿瘤异种移植物。DCLK 1 ASV过表达，与CSC标志物一起富集，可预测RCC患者的总体生存期和无复发生存期。在体外，DCLK 1 ASV能够直接刺激肾CSC的基本分子和功能特征，包括醛脱氢酶的表达、自我更新和对FDA批准的受体酪氨酸激酶和mTOR抑制剂的抗性，而DCLK 1的靶向下调逆转了这些特征。最后，用新型CBT-15单克隆抗体靶向DCLK 1 ASV阳性细胞阻断了体内RCC肿瘤发生。这些发现确立了DCLK 1作为CSC标志物，对RCC的治疗、疾病进展和生存具有影响，并证明了靶向DCLK 1的单克隆抗体针对肾CSC的治疗价值。
Renal cell carcinoma (RCC) is a common and devastating disease characterized by a hypoxic microenvironment, epithelial-mesenchymal transition and potent resistance to therapy evidencing the presence of cancer stem cells (CSCs). Various CSC markers have been studied in RCC, but overall there is limited data on their role and most markers studied have been relatively nonspecific. Doublecortin-like kinase 1 (DCLK1) is a validated CSC marker in the gastrointestinal tract and evidence for an equivalent role in other cancers is accumulating. We used bioinformatics, immunohistochemistry, flow cytometry, spheroid self-renewal and chemoresistance assays in combination with overexpression and siRNA-knockdown to study the stem cell-supportive role of DCLK1 alternative splice variants (DCLK1 ASVs) in RCC. To target tumor cells expressing DCLK1 ASVs directly, we developed a novel monoclonal antibody (CBT-15) and delivered it systemically to RCC tumor xenografts. DCLK1 ASVs were overexpressed, enriched together with CSC markers and predictive of overall and recurrence-free survival in RCC patients. In vitro, DCLK1 ASVs were able to directly stimulate essential molecular and functional characteristics of renal CSCs including expression of aldehyde dehydrogenase, self-renewal and resistance to FDA-approved receptor tyrosine kinase and mTOR inhibitors, while targeted downregulation of DCLK1 reversed these characteristics. Finally, targeting DCLK1 ASV-positive cells with the novel CBT-15 monoclonal antibody blocked RCC tumorigenesis in vivo. These findings establish DCLK1 as a CSC marker with implications for therapy, disease progression and survival in RCC and demonstrate the therapeutic value of DCLK1-targeted monoclonal antibodies against renal CSCs.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
4.8
作者：
Burgess, HA;Reiner, O
通讯作者：
Reiner, O
影响因子：
2
作者：
Li, Guorong;Badin, Gregory;Gigante, Marc
通讯作者：
Gigante, Marc
DOI：
10.1016/j.hemonc.2013.09.005
发表时间：
2014-03-01
期刊：
Hematology/oncology and stem cell therapy
影响因子：
--
作者：
Afreen, Sehar;Dermime, Said
通讯作者：
Dermime, Said
影响因子：
5.2
作者：
May, Randal;Sureban, Sripathi M.;Hoang, Nguyet;Riehl, Terrence E.;Lightfoot, Stan A.;Ramanujam, Rama;Wyche, James H.;Anant, Shrikant;Houchen, Courtney W.
通讯作者：
Houchen, Courtney W.