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

我们最近证明，双皮质素样激酶1（DCLK 1）是一种假定的结肠直肠癌， 胰腺癌干细胞标志物我们还证明了DCLK 1调节多个 致癌和肿瘤支持途径和过程。此外，siRNA介导 DCLK 1基因敲低导致胰腺癌和结直肠癌肿瘤生长停滞 异种移植DCLK 1+细胞现在强烈暗示为KRAS驱动的细胞分化的起源细胞。 最近的蛋白质组学研究表明，KRASG 12/G13的敲入 CRC细胞中的突变导致特异性DCLK 1上调。此外，DCLK 1是高度 在结直肠癌转移中表达，并预测患者生存率显著降低。 这项申请的拟议研究与两个国家癌症研究所资助的项目有关。 1. DCLK 1在胰腺导管腺癌发生中的作用我们将测试我们的 假设与实验提出了以下三个具体目标： 目的1：确定Dclk 1+细胞启动的功能和分子机制 胰腺肿瘤发生 目的2：阐明Dclk 1缺失在胰腺肿瘤发生中的多室作用。 目的3：证明靶向Dclk 1在PDAC中作为治疗方法的可行性。 2. DCLK 1在结直肠癌发生中的作用我们建议解开DCLK 1的 在KRAS突变型CRC进展中的作用，并使用以下方法评估DCLK 1靶向治疗 具体目标： 目的1：确定DCLK 1和DCLK 1+簇细胞在肿瘤发生和发展中的作用。 KRAS突变型结直肠癌。 目的2：分析DCLK 1在KRASG 12 D下游的CRC中的机制作用，以及在KRASG 12 D下游的CRC中的机制作用。 APC损失的背景。 目的3：证明在KRAS突变患者源性CRC中靶向DCLK 1的可行性 模型作为主要治疗，并克服对EGFR靶向西妥昔单抗的耐药性， 吉非替尼。 目前的建议包括创新的PDAC基因工程小鼠模型， CRC、创新细胞系和创新概念，可能会导致 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.