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

基本信息

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
项目类别：
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

项目摘要

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 Timothy C. Wang，NCI R35 胃肠道（GI）癌症最常在慢性炎症的情况下出现，因此早期进化肿瘤涉及与炎症基质的扩展上皮相互作用。王实验室专注于数十年来，在胃炎，食管炎，结肠炎和胰腺炎等多塑性状况下，以及上皮祖细胞的基质变化。实验室的最新工作表征了GI癌的起源从常驻茎和祖细胞中，在致癌过程中扩展为持续再生反应，部分是由于从不对称到对称干细胞分裂的转变。我们的实验室使用了一个组合遗传谱系跟踪，3D器官模型和单细胞RNA-sequesing与尖端结合生物信息学分析以研究正常的茎和祖细胞及其早期过渡到癌细胞。这项工作导致我们的理解发生了重大范式，例如食管的起源腺癌。虽然实验室阐明了各种基质细胞类型的作用，但主要重点是神经在调节上皮祖细胞和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在GI癌的发展中。实验室的最新初步数据表明当激活时，感觉神经诱导快速钙通量并调节肿瘤细胞的电态。在此外，实验室一直在研究未成熟的髓样细胞（IMC）的作用，即在癌症的情况下抑制肿瘤免疫（即MDSC），并由神经信号传导调节。先前的研究已有表明由炎症反射引起的Trefoil因子TFF2调节IMC并防止在我们的模型中抑制CD8+ T细胞的MDSC的开发和扩展。此外，我们最近有一直在研究髓样细胞对上皮祖细胞表观遗传变化的影响。我们的工作导致了我们现在正在寻求扩展并扩大影响的临床试验和许多合作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理解神经，髓样细胞和导致癌症的干细胞之间的串扰，以鉴定新靶标和开发新的，更有效和有针对性的疗法。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.

DOI：
10.1016/j.xpro.2024.102836
发表时间：
2024-03-15
期刊：
STAR PROTOCOLS
影响因子：
0
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

The Origins of Gastric Cancer From Gastric Stem Cells: Lessons From Mouse Models.