The role of Dclk1 in the initiation of colorectal cancer

结直肠癌(CRC)是美国癌症死亡的第三大原因，它是一种必要的 为晚期疾病患者开发更好的药物。结直肠癌肿瘤干细胞(TSCs)的特异性标志 多年来一直难以捉摸，但最近出现了强有力的数据来支持最初提议的TSC-角色 本实验室对APC突变型CRC中的DCLK1基因进行了研究。具体地说，Dclk1+簇状细胞启动 APC突变对肿瘤发生的影响：ApcMin/+模型中的谱系追踪显示 在肠道肿瘤以及炎症诱导的结肠癌模型中也是如此。引人注目的是，在ApcMin/+ 模型中，白喉毒素诱导的Dclk1+细胞缺失导致肿瘤完全崩溃，没有NO 明显的负面影响。 而APC被认为是结直肠肿瘤发生的守门人，34-70%存在失活突变 在结直肠癌中，KRAS突变也非常常见(30%-60%)，并与 显著降低总体存活率，特别是在转移性疾病中。除了限制治疗 结直肠癌患者的选择，伴随APC缺失的KRAS突变强烈增加肿瘤发生， 转移和TSC特性。DCLK1+细胞现在被认为是KRAS- 导致胰腺癌，最近的蛋白质组学研究表明KRASG12/G13突变的敲入 进入CRC细胞，导致特异性DCLK1上调20。此外，DCLK1在结直肠癌中高表达 转移，并预测患者的存活率显著降低。我们建议揭开DCLK1的S在 KRAS-突变型CRC进展和评估DCLK1靶向治疗的具体目标如下： 目的1：确定DCLK1和DCLK1+簇细胞在KRAS突变体发生和发展中的作用 结直肠癌。 目的2：剖析DCLK1在KrasG12D下游轨道交通中的作用以及在APC背景下的作用 损失。 目的3：证明在KRAS突变患者来源的结直肠癌模型中靶向DCLK1作为一种 主要治疗和克服以EGFR为靶点的西妥昔单抗和吉非替尼的耐药性。 这些研究将利用新的模型来提供DCLK1的S功能的第一个最终评估 KRAS驱动的结直肠癌的意义及其作为主要治疗靶点和辅助治疗的潜力 逆转KRAS介导的对EGFR抑制剂的耐药性。我们将以高度多元化的方式进行这些研究- 学科专家团队包括：Courtney Houchen和曲东风(DCLK1/胃肠道癌症)， Timothy Wang(DCLK1小鼠模型)、Chning Der(KRAS)、Robert Langer(生物工程)、Hans Cleves (CRC有机物)、Min Li(小鼠手术模型)和Magdalena Bieniasz(患者来源的异种移植物)。 这些研究可能会为晚期结直肠癌患者带来新的有效的治疗方法。

Colorectal cancer (CRC) is the 3rd leading cause of cancer death in the U.S, and it is a necessity to develop better drugs for those with advanced disease. Specific markers of CRC tumor stem cells (TSCs) have been elusive for many years, but recently strong data has emerged to support the TSC-role originally proposed by our lab for doublecortin-like kinase 1 (DCLK1) in APC mutant CRC. Specifically, Dclk1+ tuft cells initiate tumorigenesis in response to Apc mutation as demonstrated by lineage tracing in the ApcMin/+ model of intestinal neoplasia as well as in a model of inflammation-induced colon cancer. Strikingly, in the ApcMin/+ model, diphtheria toxin-inducible deletion of Dclk1+ cells results in a complete collapse of tumors with no apparent negative effects. While, APC is considered a gatekeeper in colorectal tumorigenesis and inactivating mutations exist in 34-70% of CRC tumors, KRAS mutations are also exceptionally common (30-60%) and associated with significantly decreased overall survival, particularly in metastatic disease. In addition to limiting therapeutic options for CRC patients, KRAS mutations accompanied by APC loss strongly increase tumorigenesis, metastasis, and TSC properties. 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 upregulation20. Moreover, DCLK1 is highly expressed in CRC metastases and predicts significantly decreased survival in patients. 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. These studies will utilize novel models to provide the first definitive assessment of the DCLK1's functional significance in KRAS-driven CRC and its potential as both a primary therapeutic target and an adjuvant to reverse KRAS-mediated resistance to EGFR inhibitors. We will pursue these studies with a highly multi- disciplinary team of experts including: Courtney Houchen and Dongfeng Qu (DCLK1/gastrointestinal cancers), Timothy Wang (DCLK1 mouse model), Channing Der (KRAS), Robert Langer (bioengineering), Hans Clevers (CRC organoids), Min Li (mouse surgery models), and Magdalena Bieniasz (patient-derived xenografts). These studies may lead to novel and effective therapies for patients with advanced CRC.