The role of DCLK1 in the initiation of pancreatic ductal adenocarcinoma

 描述(申请人提供)：胰腺导管腺癌(PDAC)是所有主要恶性肿瘤中预后最差的，5年生存率不到6%。它是发达国家癌症相关死亡的主要原因之一，也是美国癌症死亡的第四大原因。PDAC患者通常在晚期被诊断为广泛的局部肿瘤侵袭和早期转移，这是所有形式治疗的主要障碍。近年来，肿瘤干细胞(CSCs)已成为多种癌症治疗的潜在靶点。肿瘤干细胞中突变的积累增强了化疗/放疗的耐受性，消融了治疗效果，导致肿瘤复发，这是PDAC的特征。相反，由于CSCs是肿瘤细胞群体中一个独特的亚群，以这些细胞为靶点可能会导致识别治疗PDAC等难以治疗的癌症的有效药物。上皮向间充质转化(EMT)是包括PDAC在内的转移性恶性肿瘤的特征。越来越多的证据将EMT与干细胞表型联系起来，其特征是具有自我更新和分化的能力，以及表达多能性因子。我们最近证实双重皮质醇样激酶1(DCLK1)是一种可能的胰腺干细胞标记物。DCLK1在几种人类实体肿瘤中表达上调，包括结直肠癌、胰腺癌、乳腺癌和前列腺癌。我们还证明了DCLK1调节多种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异种移植瘤的生长停滞。此外，在Dclk1CreERT小鼠模型中，将KrasG12D突变引入Dclk1阳性细胞会导致胰腺癌的快速发展，这与人类PDAC是同义词。最近的研究也证实了Dclk1是胰腺和肠道中的一种特异性肿瘤干细胞标记物。基于这些发现，我们的中心假设是Dclk1启动并推动了PDAC的进展，是一种值得研究的可行的治疗方案。我们将通过以下三个特定目标提出的实验来验证我们的假设：目标1：确定Dclk1+细胞启动胰腺肿瘤发生的功能和分子机制。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。目前的提案包括创新的PDAC基因工程小鼠模型、创新的细胞系，以及可能导致对PDAC进行翻译研究的创新概念。

 DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of any major malignancy with less than a 6% 5-year survival rate. It is one of the leading causes of cancer-related death in the developed world and is the fourth leading cause of cancer death in the United States. Patients with PDAC are often diagnosed at late stages with extensive local tumor invasion and early metastasis, presenting a major obstacle to all forms of therapy. Recently, cancer stem cells (CSCs) have come into focus as potential therapeutic targets in multiple cancers. The accumulation of mutations in CSCs enhances chemo/radiation resistance ablating the effect of therapy, leading to the cancer recurrence, characteristic of PDAC. Conversely, because CSCs are a unique subset of the tumor cell population, targeting these cells may lead to the identification of effective drugs for poorly treatable cancers such as PDAC. Epithelial-to-mesenchymal transition (EMT) is a well-documented characteristic of metastatic malignancies including PDAC. There is an increasing body of evidence linking EMT to a stem cell phenotype characterized by a capacity for self-renewal and differentiation, and expression of pluripotency factors. We recently demonstrated that doublecortin-like kinase 1 (DCLK1) is a putative pancreatic stem cell marker. DCLK1 is upregulated in several human solid tumor cancers, including colorectal, pancreatic, breast and prostate cancer. 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. Moreover, introducing the KRASG12D mutation into Dclk1-positive cells in a Dclk1CreERT mouse model leads to rapid pancreatic cancer development synonymous to human PDAC. Recent studies also validated Dclk1 as a specific tumor stem cell marker in the pancreas and intestine. On the basis of these findings, our central hypothesis is that Dclk1 initiates and drives progression of PDAC and represents a viable therapeutic option worthy of investigation. 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. The current proposal includes innovative genetically engineered mouse models of PDAC, innovative cell lines, and innovative concepts that may lead to translational studies on PDAC.