Modeling Esophageal Squamous Cell Cancer Initiation

项目摘要/摘要 食管鳞状细胞癌(ESCC)占食管鳞癌的80%以上 癌症，由于早期缺乏症状，预后很差。ESCC的发展 来自鳞状上皮异型增生，是典型的组织学前驱性病变。鉴于食管鳞癌的早期诊断 可能会导致更好的预后，了解食道肿瘤的发病机制势在必行。 然而，目前的食管鳞癌模型并不适用于食管鳞癌癌前病变或肿瘤的研究。一个 以器官的生理和病理过程为特征的三维有机系统 在研究干细胞和疾病方面引起了极大的关注。因为有机化合物可以是 从手术的新鲜组织、活组织标本或冰冻组织中产生的有机物已经被 被认为是一种很有前途的工具，可以转化为癌症治疗的个性化药物或 生物标记物鉴定。根据ESCC的基因图谱，我们通过基因工程将正常 食道有机化合物(Eos)。耐人寻味的是，这种基因操作导致了EO的增殖， 去分化、细胞极性丧失和核多形性，这与早期病变相当 对ESCC的影响。此外，将这些转化的有机化合物同基因移植到小鼠体内 出现肿瘤，类似于食管鳞癌。根据初步结果，我们假设基因 EOS的操纵概括了ESCC的启动。这将通过以下两个目标来检验：AIM 1.确定食管癌癌变所需的遗传交互作用，目标2.解剖细胞和 食管鳞癌肿瘤的转录网络。共同建立一种新的小鼠食道肿瘤模型 将为研究人胚胎干细胞启动的病理生理机制奠定基础。 可能有助于提高ESCC的早期发现、预防和治疗水平。

PROJECT SUMMARY/ABSTRACT Esophageal squamous cell carcinoma (ESCC) accounts for over 80% of all cases of esophageal cancer and has a poor prognosis because of a lack of symptoms at early stages. ESCC develops from squamous dysplasia as a typical histologic precursor lesion. Given that early diagnosis of ESCC may lead to better outcomes, understanding the mechanisms of esophageal neoplasia is imperative. However, current ESCC models are not practical for the study of ESCC preneoplasia or neoplasia. A three-dimensional organoid system featuring the physiologic and pathologic processes of organs has drawn tremendous attention in studying stem cells and diseases. Because organoids can be generated from fresh tissues from surgery, biopsy specimens, or frozen tissues, organoids have been proposed as a promising tool for translation into personalized medicine for cancer treatment or biomarker identification. According to the genetic profiling of ESCC, we genetically engineered normal esophageal organoids (EOs). Intriguingly, such genetic manipulations induced the EO hyperplasia, dedifferentiation, cell polarity loss, and nuclear polymorphism, which is comparable to the early lesion of ESCC. Furthermore, syngeneic transplantation of these transformed organoids into mice developed tumors, similar to ESCC. Based on the preliminary results, we hypothesize that the genetic manipulation of EOs recapitulates ESCC initiation. This will be tested by the following two Aims: Aim 1. Determine genetic interaction required for ESCC neoplasia, Aim 2. Dissect cellular and transcriptional network of ESCC neoplasia. Together, a new model for murine esophageal neoplasia will lay the foundation for the study of pathophysiologic mechanisms of human ESCC initiation, which may lead to the improvement of early ESCC detection, prevention, and treatment.