The role of stem cells and the microenvironment in gastrointestinal cancers

干细胞和微环境在胃肠道癌症中的作用

• 批准号: 10737925
• 负责人: Timothy Cragin Wang
• 金额: $ 98.7万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-07 至 2030-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737925
• 关键词: 3-Dimensional; Area; Bioinformatics; CD8-Positive T-Lymphocytes; Chronic; Clinical Trials; Colitis; Collaborations; Colon Carcinoma; Data; Development; Elements; Epigenetic Process; Epithelium; Esophageal Adenocarcinoma; Esophagitis; Evolution; Gastritis; Genetic; Goals; Inflammation; Inflammatory; Laboratories; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of pancreas; Modeling; Myeloid Cells; Nerve; Neurons; Organoids; Pancreatitis; Peripheral Nervous System; Preneoplastic Conditions; Reflex action; Regenerative response; Role; Stromal Cells; Stromal Change; Tumor Immunity; Work; afferent nerve; cancer cell; carcinogenesis; cell type; effective therapy; gastroesophageal cancer; neoplastic cell; neurotransmission; prevent; progenitor; release of sequestered calcium ion into cytoplasm; single-cell RNA sequencing; stem; stem cell division; stem cells; targeted treatment; trefoil factor; tumor

SUMMARY/ABSTRACT Timothy C. Wang, NCI R35 Gastrointestinal (GI) cancers most often arise in the setting of chronic inflammation and thus the early evolution of tumors involves extended epithelial interactions with inflammatory stroma. The Wang laboratory has focused for decades on preneoplastic conditions such as gastritis, esophagitis, colitis and pancreatitis, and the impact of stromal changes on epithelial progenitors. Recent work from the lab has characterized the origins of GI cancers from resident stem and progenitor cells, which are expanded during carcinogenesis as a persistent regenerative response, due in part to a shift from asymmetric to symmetric stem cell division. Our lab has used a combination of genetic lineage tracing, 3D organoid models, and single cell RNA-sequencing combined with cutting edge bioinformatic analyses to investigate normal stem and progenitor cells and their early transition to cancer cells. This work has led to a major paradigm shift in our understanding, for example, of the origins of esophageal adenocarcinoma. While the lab has elucidated the role of various stromal cell types, a major focus has been on the role of nerves in modulating both epithelial progenitors as well as other stromal cells. The peripheral nervous system includes sympathetic, parasympathetic, and sensory nerves, and our lab has pioneered the study of these nerves in the development of GI cancers. Recent preliminary data from the laboratory has shown that sensory nerves when activated induce rapid calcium fluxes and modulate the electrical state of tumors cells. In addition, the laboratory has been studying the role of immature myeloid cells (IMC) that in the setting of cancer suppress tumor immunity (i.e., MDSC), and which are also modulated by neural signaling. Previous studies have shown that the trefoil factor TFF2, induced by the inflammatory reflex, modulates IMC and prevents the development and expansion of MDSC which suppress CD8+ T cells in our models. In addition, we have recently been studying the impact of myeloid cells on epigenetic changes in epithelial progenitors. Our work has led to clinical trials and numerous collaborations which we are now seeking to expand, and broaden the impact, particularly in the areas of nerves and cancer. Our proposed studies have the goal of better understanding the crosstalk between nerves, myeloid cells and stem cells that lead to cancer, in order to identify new targets and develop new, more effective and targeted therapies.

摘要/摘要 蒂莫西·王 (Timothy C. Wang)，NCI R35 胃肠道 (GI) 癌症最常出现在慢性炎症的情况下，因此早期演变 肿瘤的发生涉及上皮细胞与炎症基质的广泛相互作用。王实验室重点关注 数十年来对胃炎、食管炎、结肠炎和胰腺炎等肿瘤前病症及其影响的研究 上皮祖细胞的基质变化。实验室最近的工作揭示了胃肠道癌症的起源 来自常驻干细胞和祖细胞，它们在癌变过程中作为持续的再生细胞而扩增 反应，部分原因是干细胞分裂从不对称转向对称。我们实验室使用了一种组合 遗传谱系追踪、3D 类器官模型和单细胞 RNA 测序与尖端技术相结合 生物信息分析研究正常干细胞和祖细胞及其向癌细胞的早期转变。 这项工作使我们的理解发生了重大范式转变，例如，食管的起源 腺癌。虽然实验室已经阐明了各种基质细胞类型的作用，但主要关注点是 神经在调节上皮祖细胞以及其他基质细胞中的作用。周围神经 系统包括交感神经、副交感神经和感觉神经，我们的实验室率先研究了 这些神经参与胃肠道癌症的发展。实验室最新的初步数据表明 感觉神经被激活时会引起快速的钙通量并调节肿瘤细胞的电状态。在 此外，该实验室一直在研究未成熟骨髓细胞（IMC）在癌症中的作用 抑制肿瘤免疫（即 MDSC），并且也受到神经信号的调节。之前的研究有 研究表明，由炎症反射诱导的三叶因子 TFF2 可调节 IMC 并防止 在我们的模型中抑制 CD8+ T 细胞的 MDSC 的发育和扩增。此外，我们最近还 一直在研究骨髓细胞对上皮祖细胞表观遗传变化的影响。我们的工作导致 我们现在正在寻求扩大临床试验和大量合作，并扩大影响， 特别是在神经和癌症领域。我们提出的研究的目的是更好地了解 导致癌症的神经、骨髓细胞和干细胞之间的串扰，以便识别新的靶点和 开发新的、更有效的、更有针对性的疗法。

项目成果

Comparative genomics analysis to differentiate metabolic and virulence gene potential in gastric versus enterohepatic Helicobacter species.

• DOI: 10.1186/s12864-018-5171-2
• 发表时间: 2018-11-20
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Mannion A;Shen Z;Fox JG
• 通讯作者: Fox JG

An optimized protocol for isolation of murine pancreatic single cells with high yield and purity.

一种优化的方案，用于分离具有高产量和纯度的鼠胰腺单细胞。

• DOI: 10.1016/j.xpro.2024.102836
• 发表时间: 2024-03-15
• 期刊: STAR PROTOCOLS
• 作者: Wu, Feijing;Jiang, Zhengyu;Qian, Jin;Kobayashi, Hiroki;Waterbury, Quin T.;White, Ruth A.;Ochiai, Yosuke;Zhi, Xiaofei;Tu, Ruhong;Zheng, Biyun;Shi, Qiongyu;Zamechek, Leah B.;Wang, Timothy C.
• 通讯作者: Wang, Timothy C.

Translocation of Helicobacter hepaticus synergizes with myeloid-derived suppressor cells and contributes to breast carcinogenesis.

肝螺杆菌易位与骨髓源性抑制细胞协同作用，促进乳腺癌发生

• DOI: 10.1080/2162402x.2022.2057399
• 发表时间: 2022
• 期刊: Oncoimmunology
• 影响因子: 7.2
• 作者: Deng H;Muthupalani S;Erdman S;Liu H;Niu Z;Wang TC;Fox JG
• 通讯作者: Fox JG

Natural Transmission of Helicobacter saguini Causes Multigenerational Inflammatory Bowel Disease in C57/129 IL-10-/- Mice.

沙吉尼螺杆菌的自然传播导致 C57/129 IL-10-/- 小鼠多代炎症性肠病。

• DOI: 10.1128/msphere.00011-20
• 发表时间: 2020
• 期刊: mSphere
• 影响因子: 4.8
• 作者: Mannion,Anthony;Shen,Zeli;Feng,Yan;Puglisi,Dylan;Muthupalani,Sureshkumar;Whary,MarkT;Fox,JamesG
• 通讯作者: Fox,JamesG

IL-1β transgenic mouse model of inflammation driven esophageal and oral squamous cell carcinoma.

• DOI: 10.1038/s41598-023-39907-8
• 发表时间: 2023-08-05
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Muthupalani, Sureshkumar;Annamalai, Damodaran;Feng, Yan;Ganesan, Suresh M.;Ge, Zhongming;Whary, Mark T.;Nakagawa, Hiroshi;Rustgi, Anil K.;Wang, Timothy C.;Fox, James G.
• 通讯作者: Fox, James G.