Molecular and cellular mechanisms of Merkel Cell Carcinoma development

描述（由申请人提供）：默克尔细胞癌（MCC）是一种皮肤癌，被认为是由所谓的默克尔细胞不受控制的生长引起的，默克尔细胞是轻触反应所必需的机械受体和渗透受体。在美国，MCC的发病率每年约为1500例，而且这个数字还在不断增加。MCC是一种侵袭性癌症，高度转移，只有在早期发现时才能治愈。该领域的关键问题是更好地了解MCC的发展机制，以便能够更早地发现这种致命的癌症，并更有效地治疗患者。这些问题在人类患者中极具挑战性，因为从这些患者中获取和研究肿瘤样本存在局限性，也因为许多MCC病例是在疾病的晚期才被发现的。MCC的确切病因尚不清楚，但其发展可能与日晒和免疫抑制有关。MCC的发展也与MCPyV（默克尔细胞多瘤病毒）感染密切相关，MCPyV是2008年首次发现的一种病毒。目前的模型是，在许多MCC病例中，细胞或生物体应激为MCPyV基因组的激活创造了有利的环境，从而诱导增殖和癌变。基于不同物种的其他多瘤病毒的病毒学研究以及MCC原发肿瘤和细胞系的最新数据，我们假设抑制RB和p53肿瘤抑制通路在MCC发展的早期阶段是至关重要的。我们的第一个目标是通过使用先进的小鼠遗传学工具删除小鼠皮肤默克尔细胞中的Rb家族基因和p53来验证这一假设。我们还假设MCC起始与默克尔细胞转录谱的变化相关，部分原因是RB和p53转录调节因子失活。我们的第二个具体目标是检查默克尔细胞中RB和p53功能丧失后基因表达的变化；检测这些变化；我们将使用新的高通量RNA测序方法。如果成功，这些实验将提供第一个默克尔细胞癌的临床前模型，并将确定新的候选生物标志物和潜在的治疗靶点，以检测和治疗患者。

DESCRIPTION (provided by applicant): Merkel Cell Carcinoma (MCC) is a skin cancer that is thought to arise from the uncontrolled growth of so-called Merkel cells, which serve as mechanoreceptors and osmoreceptors essential for light-touch response. MCC incidence is about 1,500 US cases per year, and this number is continually increasing. MCC is an aggressive cancer type, highly metastatic, and it is only cured when detected early. Critical issues in the field are to better understand the mechanisms of MCC development to be able to detect this deadly cancer earlier and to treat patients more effectively. Such issues are extremely challenging to address in human patients due to limitations in acquiring and studying tumor samples from these patients and also because many cases of MCC are detected late in the course of the disease. The exact cause of MCC is still unclear, but its development may be linked to sun exposure and immunosuppression. MCC development also correlates very strongly with infection by MCPyV (Merkel Cell PolyomaVirus), a virus that was first described in 2008. The current model is that, in many cases of MCC, cellular or organism stress creates a favorable environment for activation of the MCPyV genome, resulting in the induction of proliferation and cancer initiation. Based on virology studies with other polyomaviruses in various species and recent data in MCC primary tumors and cell lines, we hypothesize that inhibition of the RB and p53 tumor suppressor pathways is critical in the early stages of MCC development. Our first aim is to test this hypothesis by deleting Rb family genes and p53 in Merkel cells in the skin of mice using advanced tools of mouse genetics. We also hypothesize that MCC initiation correlates with changes in transcriptional profiles in Merkel cells, in part because of inactivation of the RB and p53 transcriptional regulators. Our second specific aim is to examine changes in gene expression in Merkel cells upon loss of function of RB and p53 function; to detect these changes; we will use novel high-throughput RNA sequencing methods. If successful, these experiments will provide the first pre-clinical model of Merkel Cell Carcinoma and will identify novel candidate biomarkers and potential therapeutic targets to detect and treat patients.