Mechanisms and biomarkers in aberrant paligenosis-induced stomach tumorigenesis

异常异变性诱导的胃肿瘤发生的机制和生物标志物

• 批准号: 10411740
• 负责人: Jason C Mills
• 金额: $ 20.4万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10411740
• 关键词: 3-Dimensional; Acids; Affect; Atrophic; Atrophic Gastritis; Autophagocytosis; Back; Bacteria; Basic Science; Bioinformatics; Biological Markers; CD44 gene; Cancerous; Cell Cycle; Cell Cycle Stage; Cell Differentiation process; Cells; Cessation of life; Chief Cell; China; Chinese People; Chronic; Clinical; Clinical Data; Collaborations; Complex; DNA Damage; DNA Markers; Data; Dose; Dysplasia; Ensure; Enzymes; Event; Gastric Adenocarcinoma; Gastric Glands; Gastric Parietal Cells; Gene Expression; Gene Mutation; Generations; Genes; Genetic Models; Genomic Instability; Genomics; Glandular Cell; Goals; Growth; Health; Helicobacter pylori; High Prevalence; Human; Image; Inflammation; Injury; Lead; Lesion; Licensing; Link; Lysosomes; Malignant Neoplasms; Mediating; Medical; Metabolic; Metaplasia; Metaplastic Cell; Methylnitrosourea; Modeling; Molecular; Mus; Mutagens; Mutant Strains Mice; Mutation; Neoplasms; Organelles; Organoids; Patients; Pattern; Procedures; Process; Production; Proliferating; Protocols documentation; Regulation; Resolution; Resources; Risk; Role; S Phase; Sampling; Signal Transduction; Stomach; TP53 gene; Tamoxifen; Testing; Time; Tissue Microarray; Tissues; Translating; Universities; University resources; Ursidae Family; cancer risk; cell injury; collaborative approach; data repository; exome sequencing; gastric tumorigenesis; gastrointestinal; global health; inhibitor/antagonist; innovation; malignant stomach neoplasm; mouse model; mutant; novel; paligenosis; patient population; premalignant; progenitor; programs; recruit; repaired; response; response to injury; spasmolytic polypeptide; transcriptome; transcriptome sequencing; translational study; tumor; tumor progression; tumorigenesis; wound healing

PROJECT SUMMARY We study formation of upper gastrointestinal premalignant lesions, as well as their progression to neoplasia. A key premalignant lesion in gastric cancer, pseudopyloric or Spasmolytic Polypeptide Expressing Metaplasia (SPEM), occurs when chronic inflammation (usually via the bacterium Helicobacter pylori) leads to death (atrophy) of acid-secreting parietal cells and a change in differentiation pattern of the other key gastric gland lineage, the zymogenic chief cell (ZC). We and others have shown that ZCs in SPEM become proliferative and metaplastic. They do so via a sequence of molecular-cellular events that is conserved across many tissues and species in scenarios where mature cells are recruited back into the cell cycle in response to tissue damage. Thus, ZCs undergoing metaplasia undergo an evolutionarily conserved program, termed paligenosis. In paligenosis ZCs: first degrade/recycle their differentiated cell specialized components (Stage 1), then induce expression of more progenitor-like genes (eg. Sox9 = Stage 2), and ultimately re-enter the cell cycle (Stage 3). Metaplasia can resolve as tissue is repaired or become chronic and increase risk for progression to dysplasia and cancer. We have shown that paligenosis is governed by dynamic changes in mTORC1, the key cellular translational control complex. mTORC1 is elevated at baseline in ZCs to drive production of digestive enzymes; it shuts off at Stage 1 and reactivates at Stage 3. Without mTORC1, paligenosis stops at Stage 2 with cells looking metaplastic but unable to enter the S-phase. Here, we explore the mechanisms underlying progression through paligenosis. Our overarching hypothesis is that paligenosis is a licensing procedure to ensure that old cells, which may have accumulated mutations and have damaged organelles, undergo a strict error-checking protocol before being allowed to reenter the cell cycle. Errors in paligenosis may lead to tumors as cells with mutations may inappropriately proliferate. In the current proposal, we focus on mechanisms regulating Stage 1 and Stage 3 and determine effects on tumorigenesis with correlation to humans. We undertake these studies with our long-standing collaborators at China Medical University in Shenyang, China. They provide vast tissue databanks of normal, metaplastic, and cancerous stomach tissue with accompanying clinical data. And they have established pipelines for sequencing and bioinformatic analysis. Our Aims are: 1) to determine effects of cells either being stuck or skipping Stage 1; 2) to elucidate the effects of altering the p53-mTORC1 hub that determines Stage 3; and 3) to translate our findings towards human relevance using long-term tumorigenesis models with mouse mutants in cycles of paligenosis as well as correlation in mouse/human ex vivo organoids and in tissue microarrays of ~1000 human patients. Together, our combined US-China teams will bring resources and expertise to bear on a global, understudied health problem with particularly high prevalence in Northeastern China: gastric cancer.

项目概要 我们研究上消化道癌前病变的形成及其进展为肿瘤。一个 胃癌、假幽门或解痉多肽表达化生中的关键癌前病变 (SPEM)，当慢性炎症（通常通过幽门螺杆菌）导致死亡时发生 胃泌酸壁细胞（萎缩）和其他关键胃腺分化模式的变化 谱系，酶原主细胞（ZC）。我们和其他人已经证明 SPEM 中的 ZC 会增殖并且 化生。它们通过一系列在许多组织中保守的分子细胞事件来做到这一点 以及成熟细胞响应组织而被招募回细胞周期的情况下的物种 损害。因此，经历化生的 ZC 经历了一个进化上保守的程序，称为异变。 在多变性 ZC 中：首先降解/回收其分化的细胞特化成分（第 1 阶段），然后诱导 表达更多类祖基因（例如 Sox9 = 第 2 阶段），并最终重新进入细胞周期（第 3 阶段）。 化生可以随着组织的修复而消退或变成慢性，并增加进展为不典型增生的风险 和癌症。我们已经证明，多变性是由 mTORC1 的动态变化控制的，mTORC1 是关键的细胞因子。 翻译控制复合体。 mTORC1 在 ZC 中的基线升高，以驱动消化液的产生 酶；它在第 1 阶段关闭并在第 3 阶段重新激活。如果没有 mTORC1，多变性会在第 2 阶段停止 细胞看起来化生但无法进入 S 期。 在这里，我们探讨了通过异变性进展的机制。我们的首要任务 假说是，仿生是一种许可程序，以确保可能已经积累的旧细胞 突变并损坏细胞器，在被允许之前要经过严格的错误检查协议 重新进入细胞周期。异基因错误可能会导致肿瘤，因为带有突变的细胞可能会不恰当地 增生。在当前的提案中，我们重点关注第一阶段和第三阶段的监管机制，并确定 对与人类相关的肿瘤发生的影响。我们利用我们长期的经验来开展这些研究 中国沉阳中国医科大学的合作者。他们提供了大量的正常组织数据库， 化生和癌性胃组织以及随附的临床数据。并且他们已经建立了 用于测序和生物信息分析的管道。我们的目标是：1）确定细胞的影响 卡住或跳过第 1 阶段； 2) 阐明改变决定第 3 阶段的 p53-mTORC1 中枢的影响； 3）使用小鼠长期肿瘤发生模型将我们的发现转化为人类相关性 多变周期中的突变体以及小鼠/人类离体类器官和组织中的相关性 约 1000 名人类患者的微阵列。 我们的美中联合团队将共同带来资源和专业知识，为全球、 中国东北地区患病率特别高的未被充分研究的健康问题：胃癌。