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:
- 金额:$ 98.7万
- 依托单位:
- 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:
- 关键词:3-DimensionalAreaBioinformaticsCD8-Positive T-LymphocytesChronicClinical TrialsColitisCollaborationsColon CarcinomaDataDevelopmentElementsEpigenetic ProcessEpitheliumEsophageal AdenocarcinomaEsophagitisEvolutionGastritisGeneticGoalsInflammationInflammatoryLaboratoriesMalignant NeoplasmsMalignant neoplasm of gastrointestinal tractMalignant neoplasm of pancreasModelingMyeloid CellsNerveNeuronsOrganoidsPancreatitisPeripheral Nervous SystemPreneoplastic ConditionsReflex actionRegenerative responseRoleStromal CellsStromal ChangeTumor ImmunityWorkafferent nervecancer cellcarcinogenesiscell typeeffective therapygastroesophageal cancerneoplastic cellneurotransmissionpreventprogenitorrelease of sequestered calcium ion into cytoplasmsingle-cell RNA sequencingstemstem cell divisionstem cellstargeted treatmenttrefoil factortumor
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:
- 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:
- 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.
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:
- 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
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:
- 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
The Origins of Gastric Cancer From Gastric Stem Cells: Lessons From Mouse Models.
- DOI:10.1016/j.jcmgh.2017.01.013
- 发表时间:2017-05
- 期刊:
- 影响因子:7.2
- 作者:Hayakawa Y;Fox JG;Wang TC
- 通讯作者:Wang TC
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Timothy Cragin Wang其他文献
Timothy Cragin Wang的其他文献
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{{ truncateString('Timothy Cragin Wang', 18)}}的其他基金
Gastrin Regulation of Gastric Antral Stem and Corpus Progenitor Cells
胃窦干细胞和胃体祖细胞的胃泌素调节
- 批准号:
10490463 - 财政年份:2021
- 资助金额:
$ 98.7万 - 项目类别:
Gastrin Regulation of Gastric Antral Stem and Corpus Progenitor Cells
胃窦干细胞和胃体祖细胞的胃泌素调节
- 批准号:
10686228 - 财政年份:2021
- 资助金额:
$ 98.7万 - 项目类别:
Gastrin Regulation of Gastric Antral Stem and Corpus Progenitor Cells
胃窦干细胞和胃体祖细胞的胃泌素调节
- 批准号:
10367556 - 财政年份:2021
- 资助金额:
$ 98.7万 - 项目类别:
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:
10532704 - 财政年份:2016
- 资助金额:
$ 98.7万 - 项目类别:
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:
10307622 - 财政年份:2016
- 资助金额:
$ 98.7万 - 项目类别:
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:
9186833 - 财政年份:2016
- 资助金额:
$ 98.7万 - 项目类别:
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:
10059178 - 财政年份:2016
- 资助金额:
$ 98.7万 - 项目类别:
Quiescent Dclk1+ stem cells in the mouse intestine
小鼠肠道中的静态 Dclk1 干细胞
- 批准号:
8865612 - 财政年份:2013
- 资助金额:
$ 98.7万 - 项目类别:
Quiescent Dclk1+ stem cells in the mouse intestine
小鼠肠道中的静态 Dclk1 干细胞
- 批准号:
8577370 - 财政年份:2013
- 资助金额:
$ 98.7万 - 项目类别:
Quiescent Dclk1+ stem cells in the mouse intestine
小鼠肠道中的静态 Dclk1 干细胞
- 批准号:
8547458 - 财政年份:2012
- 资助金额:
$ 98.7万 - 项目类别:
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