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.

项目摘要/摘要 食管鳞状细胞癌（ESCC）占食管所有病例的80％以上 癌症，预后较差，因为早期缺乏症状。 ESCC发展 从鳞状发育不良作为典型的组织学前体病变。鉴于ESCC的早期诊断 可能导致更好的结果，了解食管肿瘤的机制是必须的。 但是，当前的ESCC模型对于研究ESCC肿瘤或肿瘤的研究是不切实际的。一个 具有器官的生理和病理过程的三维器官系统具有 在研究干细胞和疾病中引起了极大的关注。因为器官可以是 由手术，活检标本或冷冻组织的新鲜组织产生的类器官 提议作为一种有前途的工具，用于转化为个性化医学进行癌症治疗或 生物标志物识别。根据ESCC的基因分析，我们对正常进行了基因设计 食管类器官（EOS）。有趣的是，这种遗传操纵诱导了EO增生， 去分化，细胞极性丧失和核多态性，与早期病变相当 ESCC。此外，将这些转化的类器官的合成性移植到小鼠中 开发的肿瘤，类似于ESCC。基于初步结果，我们假设遗传 EOS的操作概括了ESCC的启动。这将通过以下两个目的对此进行测试：目标 1。确定ESCC肿瘤所需的遗传相互作用，AIM 2。剖析细胞和 ESCC肿瘤的转录网络。一起，是鼠食管肿瘤的新模型 将奠定研究人ESCC启动的病理生理机制的基础，这 可能导致早期ESCC检测，预防和治疗的改善。