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: 10490897
• 负责人: Jason C Mills
• 金额: $ 19.99万
• 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/10490897
• 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 population; 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; 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.

项目摘要 我们研究上胃肠道前病变的形成及其向肿瘤的发展。一个 胃癌，伪层或痉挛性多肽表达化生的关键病变 （SPEM），发生慢性炎症（通常通过细菌幽门螺杆菌）导致死亡时发生 （萎缩）分泌酸的顶叶细胞和其他关键胃腺的分化模式的变化 谱系，酶促的主要细胞（ZC）。我们和其他人已经表明，SPEM中的ZC变得更加生动，并且 变质。他们通过一系列分子 - 细胞事件进行此操作，这些事件在许多组织中保守 和物种在响应组织中招募成熟细胞回到细胞周期的情况下 损害。因此，ZC经历了化生的ZC经历了一个进化保守的程序，称为paligeneniso。 在Paligeneniso ZCS中：首先降解/回收其分化的细胞专用组件（第1阶段），然后诱导 表达更多的祖细胞样基因（例如SOX9 =阶段2），并最终重新进入细胞周期（第3阶段）。 随着组织的修复或变为慢性，可以解决变质，并增加发展为发育不良的风险 和癌症。我们已经表明，丙二买症受钥匙细胞MTORC1的动态变化控制 翻译控制综合体。 MTORC1在ZCS的基线时升高以驱动消化率的产生 酶；它在第1阶段关闭并在第3阶段重新激活。没有mtorc1，paligenisoise停在第2阶段 细胞看上去具有变质，但无法进入S期。 在这里，我们探讨了通过丙肾上腺炎进展的机制。我们的总体 假设是，邻位症是一种许可程序，以确保旧细胞（可能积累的旧细胞） 突变并损坏细胞器，在被允许之前进行严格检查的错误检查协议 重新进入细胞周期。由于具有突变的细胞可能不当 增生。在当前的建议中，我们专注于调节第1阶段和第3阶段的机制并确定 与人类相关的肿瘤发生的影响。我们以我们的长期来进行这些研究 中国中国医科大学的合作者。他们提供正常的庞大组织数据库 伴随临床数据的化生和癌性胃组织。他们已经建立了 测序和生物信息学分析的管道。我们的目标是：1）确定细胞的影响 卡住或跳过第1阶段； 2）阐明改变了决定第3阶段的p53-MTORC1中心的影响； 3）使用长期肿瘤发生模型将我们的发现转化为人类相关性 孤生病周期中的突变体以及小鼠/人类外体和组织中的相关性 〜1000名人类患者的微阵列。 我们合并的美国团队将带来资源和专业知识，以实现全球， 中国东北部的健康问题研究尤其高，胃癌。