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的不受控制的生长引起的，所述细胞作为光接触反应所必需的机械感受器和光感受器。MCC的发病率在美国每年约为1,500例，而且这个数字还在不断增加。MCC是一种侵袭性癌症类型，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发展的机制，以便能够更早地检测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解决极具挑战性，这是由于在从这些患者获取和研究肿瘤样品方面的限制，并且还因为许多MCC病例在疾病过程的后期被检测到。MCC的确切原因尚不清楚，但其发展可能与阳光照射和免疫抑制有关。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年首次描述的一种病毒。目前的模型是，在MCC的许多情况下，细胞或生物体应激为MCPyV基因组的激活创造了有利的环境，导致增殖和癌症起始的诱导。基于病毒学研究与其他多瘤病毒在各种物种和MCC原发性肿瘤和细胞系的最新数据，我们假设RB和p53肿瘤抑制通路的抑制是至关重要的MCC发展的早期阶段。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中默克尔细胞中的Rb家族基因和p53来验证这一假设。我们还假设MCC启动与默克尔细胞中转录谱的变化相关，部分原因是RB和p53转录调节因子的失活。我们的第二个具体目标是检查RB和p53功能丧失后默克尔细胞中基因表达的变化;为了检测这些变化，我们将使用新的高通量RNA测序方法。如果成功，这些实验将提供默克尔细胞癌的第一个临床前模型，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。 公共卫生相关性：默克尔细胞癌（MCC）是一种侵袭性神经内分泌型皮肤癌，其发病率正在增加，死亡率非常高。新出现的证据表明RB和p53肿瘤抑制因子在MCC细胞中失活。我们建议删除成年小鼠皮肤中默克尔细胞中的Rb和p53基因，以生成和分析这种致命癌症的小鼠模型。在患者中类似MCC的小鼠病变的发展将提供一个临床前系统来研究MCC发展的分子和细胞机制，并可能最终提供预防和治疗患者MCC的新方法。

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. PUBLIC HEALTH RELEVANCE: Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine type of skin cancer whose incidence is increasing and mortality risk very high. Emerging evidence indicates that the RB and p53 tumor suppressors are inactivated in MCC cells. We propose to delete the Rb and p53 genes in Merkel cells in the skin of adult mice to generate and analyze a mouse model for this deadly cancer. The development of mouse lesions resembling MCC in patients would provide a pre-clinical system to investigate the molecular and cellular mechanisms underlying MCC development and may ultimately provide novel means to prevent and treat MCC in patients.