Modeling Esophageal Squamous Cell Cancer Initiation

食管鳞状细胞癌发生建模

• 批准号: 10360687
• 负责人: Jae-Il Park
• 金额: $ 8.1万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10360687
• 关键词: 3-Dimensional; Alleles; Animal Model; Attention; Biological Models; Biopsy Specimen; Cancer Biology; Cell Polarity; Detection; Diagnosis; Disease; Dysplasia; Early Diagnosis; Epithelial; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagus; Event; Fostering; Foundations; Freezing; Fresh Tissue; Genetic; Genetic Engineering; Genetic Polymorphism; Genetic Transcription; Health; Heterogeneity; Histologic; Human; Hyperplasia; Isogenic transplantation; KRASG12D; Knock-out; Knowledge; Lead; Lesion; MAP Kinase Gene; Maintenance; Malignant neoplasm of esophagus; Mission; Modeling; Molecular; Morphology; Mus; Mutation; Neoplasms; Nuclear; Operative Surgical Procedures; Organ; Organoids; Outcome; Outcomes Research; Pathologic Processes; Pathway interactions; Physiological Processes; Play; Prevention; Prognosis; Public Health; Radiation therapy; Reagent; Recipe; Regenerative capacity; Reporting; Research; Role; Sampling; Symptoms; System; TP53 gene; Testing; Therapeutic; Tissues; Translating; Translations; United States National Institutes of Health; base; biomarker identification; cancer biomarkers; cancer initiation; cancer therapy; chemoradiation; chemotherapy; drug discovery; early detection biomarkers; esophageal squamous cell cancer; genetic manipulation; genetic profiling; innovation; mouse model; personalized medicine; programs; stem cells; tool; tumor; tumorigenesis

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.

项目总结/摘要 食管鳞状细胞癌（ESCC）占所有食管癌病例的80%以上。 癌症，并且由于在早期阶段缺乏症状而预后不良。ESCC开发 鳞状上皮异常增生是典型的组织学前驱病变鉴于早期诊断食管癌 可能导致更好的结果，了解食管肿瘤的机制是必要的。 然而，目前的ESCC模型对于ESCC癌前病变或瘤形成的研究是不实用的。一 以器官的生理和病理过程为特征的三维类器官系统， 在干细胞和疾病的研究中引起了极大的关注。因为类器官可以 从来自手术的新鲜组织、活组织检查标本或冷冻组织产生，类器官已经被 被提议作为一种有前途的工具，用于转化为个性化的癌症治疗药物， 生物标志物鉴定根据ESCC的基因图谱，我们基因工程正常 食管类器官（EOs）。有趣的是，这种基因操作诱导了EO增生， 去分化、细胞极性丧失和核多态性，这与早期病变相当 的ESCC。此外，将这些转化的类器官同基因移植到小鼠中， 发展成肿瘤，类似于ESCC。根据初步结果，我们假设， 对E0的操纵再现了ESCC的起始。这将通过以下两个目标进行检验： 1.确定ESCC瘤形成所需的遗传相互作用，目的2。解剖细胞， ESCC肿瘤形成的转录网络。总之，一种新的小鼠食管肿瘤模型 为进一步研究食管鳞癌发生的病理生理机制奠定基础， 可能导致早期ESCC检测，预防和治疗的改善。