Mechanisms and biomarkers in aberrant paligenosis-induced stomach tumorigenesis

项目摘要 我们研究上消化道癌前病变的形成，以及它们向肿瘤的发展。一 胃癌关键癌前病变假幽门或痉挛性多肽表达化生 当慢性炎症（通常通过细菌幽门螺杆菌）导致死亡时， 泌酸壁细胞（萎缩）和其他关键胃腺分化模式的变化 系，酶原主细胞（ZC）。我们和其他人已经表明，在SPEM中的ZCs变得增殖， 化生的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 和物种的情况下，成熟细胞被招募回细胞周期，以响应组织 损害因此，经历化生的ZCs经历进化上保守的程序，称为paligenosis。 在发褐质病ZC中：首先降解/再循环其分化的细胞特化组分（第1阶段），然后诱导 更多祖细胞样基因的表达（例如，Sox 9 =第2阶段），并最终重新进入细胞周期（第3阶段）。 化生可随着组织修复而消退或变为慢性，并增加进展为异型增生的风险 和癌症我们已经表明，黄褐斑是由mTORC 1的动态变化，关键的细胞 翻译控制复合物在ZC中，mTORC 1在基线时升高，以驱动消化道分泌物的产生。 它在第一阶段关闭，在第三阶段重新激活。如果没有mTORC 1，则在第2阶段停止发生发灰病 细胞看起来是化生的，但不能进入S期。 在这里，我们探讨通过paligenosis进展的机制。我们的总体 有一种假说认为，褐变是一种许可程序，以确保可能积累的衰老细胞 突变和细胞器受损，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。在paligenosis错误可能会导致肿瘤的细胞突变可能不适当 增殖。在目前的提案中，我们侧重于调节第一阶段和第三阶段的机制，并确定 与人类相关的肿瘤发生的影响。我们进行这些研究与我们的长期 中国沈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伴随的临床数据。他们建立了 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， 卡住或跳过阶段1; 2）阐明改变决定阶段3的p53-mTORC 1枢纽的影响; 和3）使用小鼠的长期肿瘤发生模型将我们的发现转化为人类相关性。 在小鼠/人离体类器官和组织中， 约1000名人类患者的微阵列。 我们的中美团队将携起手来， 在中国东北地区发病率特别高的未充分研究的健康问题：胃癌。

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.