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.

项目总结 我们研究上消化道癌前病变的形成，以及它们向肿瘤的进展。一个 胃癌的关键癌前病变，假幽门或痉挛溶解多肽表达化生 (SPEM)，当慢性炎症(通常通过幽门螺杆菌)导致死亡时发生 胃壁酸分泌细胞萎缩和其他关键胃腺分化模式的改变 谱系，产酶主细胞(ZC)。我们和其他人已经证明了SPEM中的ZCs变得增殖和 化生组织。它们通过一系列在许多组织中保守的分子-细胞事件来实现这一点 以及在成熟细胞被招募回细胞周期以响应组织的情况下的物种 损坏。因此，经历化生的ZCS经历了一种进化上保守的程序，称为掌状症。 帕金森病的ZCS：首先降解/回收其分化的细胞特化成分(阶段1)，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(阶段3)。 化生可随着组织修复或慢性化而消退，并增加进展为异型增生的风险。 和癌症。我们已经证明，掌状症是由关键细胞mTORC1的动态变化控制的 翻译控制复合体。在ZCS中mTORC1在基线水平升高以推动消化系统的产生 酶；它在阶段1关闭并在阶段3重新激活。如果没有mTORC1，手掌畸形在阶段2停止 细胞看起来化生，但无法进入S期。 在这里，我们探索通过掌症进展的潜在机制。我们最重要的是 假说是，掌叶萎缩症是一种许可程序，以确保可能积累的旧细胞 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。手掌畸形的错误可能导致肿瘤，因为带有突变的细胞可能会不适当地 扩散。在目前的提案中，我们将重点放在调节阶段1和阶段3的机制上，并确定 与人类相关的对肿瘤发生的影响。我们长期致力于这些研究。 沈阳中国医科大学的合作者中国。它们提供了巨大的正常组织数据库， 化生和癌变的胃组织，并附临床资料。他们已经确立了 用于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 滞留或跳过阶段1；2)阐明改变决定阶段3的p53-mTORC1枢纽的影响； 以及3)使用小鼠的长期肿瘤发生模型将我们的发现转化为与人类的相关性 人/鼠体外有机体和组织中的突变型及其相关性 约1000名人类患者的基因芯片。 我们联合起来的美国-中国团队将带来资源和专业知识， 中国东北地区发病率特别高的健康问题：胃癌。