The role of DCLK1 in the initiation of pancreatic ductal adenocarcinoma and colorectal cancer

我们最近证实双重皮质醇样激酶1(DCLK1)是一种可能的结直肠和 胰腺癌干细胞标志物。我们还证明了DCLK1调节多个 致癌和肿瘤支持途径和过程。此外，siRNA介导的 DCLK1基因敲除导致胰腺癌和结直肠癌生长停滞 异种移植物。DCLK1+细胞现在被认为是KRAS驱动的起源细胞 胰腺癌，以及最近的蛋白质组学研究表明，KRASG12/G13的敲入 进入CRC细胞的突变导致特定的DCLK1上调。此外，DCLK1还具有很高的 在结直肠癌转移中表达，并预测患者的存活率显著降低。 这项申请的拟议研究涉及NCI资助的两个项目。 1.DCLK1在胰腺导管腺癌发生中的作用我们将测试我们的 假设和实验提出了以下三个具体目标： 目的1：确定Dclk1+细胞启动的功能和分子机制 胰腺肿瘤的发生。 目的2：探讨Dclk1缺失在胰腺肿瘤发生中的多区间作用。 目的：探讨以Dclk1为靶点的PDAC治疗方法的可行性。 2.DCLK1在结直肠癌发生中的作用我们建议拆解DCLK1的S KRAS突变型结直肠癌进展中的作用及DCLK1靶向治疗的评估 具体目标： 目的1：确定DCLK1和DCLK1+簇状细胞在骨肉瘤发生发展中的作用 KRAS基因突变的结直肠癌。 目的2：剖析DCLK1在KrasG12D下游的轨道交通中的S机制作用 APC丢失的背景。 目的3：论证靶向DCLK1治疗KRAS突变患者来源的结直肠癌的可行性 模型作为主要治疗方法，并克服对EGFR靶向西妥昔单抗和 吉非替尼。 目前的建议包括创新的PDAC基因工程小鼠模型和 CRC、创新的细胞系和可能导致翻译研究的创新概念 PDAC和CRC。

We recently demonstrated that doublecortin-like kinase 1 (DCLK1) is a putative colorectal and pancreatic cancer stem cell marker. We also demonstrated that DCLK1 regulates multiple oncogenic and tumor supporting pathways and processes. Furthermore, siRNA mediated knockdown of DCLK1 results in growth arrest of pancreatic and colorectal cancer tumor xenografts. The DCLK1+ cell is now strongly implicated as a cell-of-origin for KRAS-driven pancreatic cancer, and recent proteomic studies demonstrate that knock-in of KRASG12/G13 mutations into CRC cells results in specific DCLK1 upregulation. Moreover, DCLK1 is highly expressed in CRC metastases and predicts significantly decreased survival in patients. The proposed studies for this application are related to two NCI-funded projects. 1. The role of DCLK1 in the initiation of pancreatic ductal adenocarcinoma. We will test our hypotheses with the experiments proposed in the following three specific aims: Aim 1: To determine the functional and molecular mechanisms through which Dclk1+ cells initiate pancreatic tumorigenesis. Aim 2: To delineate the multi-compartmental role of Dclk1 deletion in pancreatic tumorigenesis. Aim 3: To demonstrate the feasibility of targeting Dclk1 in PDAC as a therapeutic approach. 2. The role of DCLK1 in the initiation of colorectal cancer. We propose to unravel DCLK1's role in KRAS-mutant CRC progression and assess DCLK1-targeted therapies with the following Specific Aims: Aim 1: Determine the role of DCLK1 and the DCLK1+ tuft cell in the initiation and progression of KRAS-mutant colorectal cancer. Aim 2: Dissect DCLK1's mechanistic role in CRC downstream of KRASG12D and in the background of APC loss. Aim 3: Demonstrate the feasibility of targeting DCLK1 in KRAS-mutant patient-derived CRC models as a primary therapy and to overcome resistance to EGFR-targeted cetuximab and gefitinib. The current proposals include innovative genetically engineered mouse models of PDAC and CRC, innovative cell lines, and innovative concepts that may lead to translational studies on PDAC and CRC.