FLOAT System to Study Salivary Gland Cancer Invasion
FLOAT 系统研究唾液腺癌侵袭
基本信息
- 批准号:9763563
- 负责人:
- 金额:$ 21.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-14 至 2020-07-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAcinar CellAddressAnimal ModelArchitectureAttentionAutophagocytosisBioinformaticsCRISPR/Cas technologyCancer BiologyCancer PatientCell Culture TechniquesCellsColorComorbidityComplexConnective TissueDataDepositionDesmoplasticDietDiseaseDistantDsRedDuctal Epithelial CellEnvironmentExtracellular MatrixFatty acid glycerol estersFibroblastsFibrosisFluorescenceGene ExpressionGenesGenetic TranscriptionGlandGoalsGreen Fluorescent ProteinsHeterogeneityHumanImmuneImmunocompetentImplantInflammationInvadedInvestigationLabelLasersLesionLifeLinkLipidsLocalized Malignant NeoplasmMalignant NeoplasmsMalignant neoplasm of salivary glandMass Spectrum AnalysisMethodsModelingMolecularMonitorMusNeoplasmsObesityOrganPathway interactionsPlayPrevalenceProcessPrognostic MarkerProteinsReportingResearchResearch PersonnelResidual stateResourcesRoleSalivarySalivary Gland NeoplasmsSalivary GlandsSiteSolidSpectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationStromal CellsStructureSubmandibular glandSucroseSystemTestingTherapeuticTimeTissue imagingTissuesTransgenic AnimalsTransgenic ModelTransplantationTumor Cell InvasionWorkallotransplantcancer cellcancer typedesigndiagnostic biomarkerfollow-upgenetic signaturehost neoplasm interactionimprovedin vitro Modelin vivoinnovationinsightionizationmigrationneoplastic cellnovel diagnosticsnovel strategiesnovel therapeuticsoutcome forecastpreservationprognostic assaysrecruitresponsespatiotemporalthree dimensional structuretransplant modeltreatment strategytumortumor microenvironmenttumor progression
项目摘要
The goal of this R21 is to use our newly developed dual-color Fluorescence-tracing Orthotopic
AlloTransplantation (FLOAT) system to investigate the molecular mechanisms underlying salivary gland
cancer (SGC) progression. Bioinformatics studies of human SGC have identified putative molecular pathways
that regulate tumor invasion, but follow-up analysis has proved challenging. Cell culture models are limited by
the lack of a native tumor microenvironment and transgenic animal models are limited by resource-intensive
methods and difficulties distinguishing tumor cells from the surrounding stroma. Therefore, new approaches
that allow researchers to rapidly test molecular hypotheses, while preserving the native 3D structure of the
tumor microenvironment, are needed. Furthermore, these models need to consider the impact of other
comorbidities in distant sites, such as obesity. Our proposal will address this need using the FLOAT system, a
simple and experimentally tractable orthotopic transplantation model, which allows researchers to visualize
implanted salivary tumor cells and the adjacent microenvironment, to accurately model many aspects of in vivo
SGC progression. This system utilizes DsRed fluorescence to label salivary tumor cells, which are transplanted
into the salivary glands of green fluorescent protein-expressing mice. Dual-color fluorescence allows
researchers to rapidly evaluate the tumor cells relative to the adjacent stroma. Our preliminary data
demonstrate that the FLOAT system was useful for demonstrating that intrinsic tumor autophagy capacity
modulates the architecture of tumor-bearing glands and survival. We will now use the FLOAT system to
evaluate how obesity promotes local invasion of primary SGC lesions in vivo. Local invasion is required for
SGC progression, but this multifaceted process is not well understood. Also, although changes in both tumor
cells and the surrounding matrix have been reported during cancer progression, a direct mechanistic link
between diet-induced obesity and accelerated SGC progression has not been established. We hypothesize
that diet-induced obesity exacerbates SGC local invasion by inducing changes in the tumor
microenvironment that permit or enhance local invasion. Given the crucial role of the tumor
microenvironment in cancer progression, we further predict that the effect of diet-induced obesity on the type
and activity of cells in the tumor microenvironment facilitates SGC invasion. In Aim 1, we will use the FLOAT
system to test the effects of diet-induced obesity on SGC local invasion, gene expression, and lipid profiles.
This Aim includes 3D matrix-assisted laser desorption/ionization (MALDI)-tissue-imaging mass spectrometry
(TIMS) analysis of lipid profile heterogeneity in the invading tumor. In Aim 2, we will use the FLOAT system to
test the effects of diet-induced obesity on fibrosis and inflammation in the microenvironment. The FLOAT
system represents a powerful first step for both visualizing and distinguishing the heterogeneous components
of host-tumor interaction during local invasion and a new system for efficiently testing novel therapeutics.
此R21的目标是使用我们新开发的双色双折射跟踪原位
同种异体移植(FLOAT)系统,以研究唾液腺的分子机制
胃癌(SGC)进展。人类SGC的生物信息学研究已经确定了推定的分子途径
调节肿瘤侵袭,但后续分析已证明具有挑战性。细胞培养模型受限于
由于缺乏天然肿瘤微环境和转基因动物模型,
区分肿瘤细胞和周围间质的方法和困难。因此,新方法
这使研究人员能够快速测试分子假设,同时保留了细胞的天然3D结构。
肿瘤微环境是必需的。此外,这些模型还需要考虑其他因素的影响。
远处的合并症,如肥胖。我们的建议将使用浮动系统来解决这一需求,
一个简单的,实验上易于处理的原位移植模型,它允许研究人员可视化
植入的唾液腺肿瘤细胞和邻近的微环境,以准确地模拟体内的许多方面,
SGC进展。该系统利用DsRed荧光标记唾液肿瘤细胞,
进入绿色荧光蛋白表达小鼠的唾液腺。双色荧光允许
研究人员快速评估肿瘤细胞相对于邻近基质。我们的初步数据
证明FLOAT系统可用于证明固有的肿瘤自噬能力,
调节肿瘤腺体的结构和存活。我们现在将使用FLOAT系统来
评估肥胖如何促进体内原发性SGC病变的局部侵袭。需要局部侵入,
SGC进展,但这个多方面的过程还没有得到很好的理解。此外,虽然肿瘤的变化
细胞和周围的基质已经报道在癌症进展过程中,一个直接的机制联系,
饮食诱导的肥胖和加速的SGC进展之间的关系尚未确定。我们假设
饮食诱导的肥胖通过诱导肿瘤的变化加剧了SGC局部侵袭,
微环境允许或增强局部侵入。考虑到肿瘤的重要作用
微环境在癌症进展中的作用,我们进一步预测饮食诱导的肥胖对癌症类型的影响。
并且肿瘤微环境中的细胞活性促进SGC侵袭。在目标1中,我们将使用浮动
系统来测试饮食诱导的肥胖对SGC局部侵袭、基因表达和脂质谱的影响。
该Aim包括3D基质辅助激光解吸/电离(MALDI)-组织成像质谱
在侵袭性肿瘤中脂质谱异质性的TIMS分析。在目标2中,我们将使用FLOAT系统,
测试饮食诱导的肥胖对微环境中纤维化和炎症的影响。浮子
系统代表了可视化和区分异构组件的强大的第一步
在局部侵袭过程中宿主-肿瘤相互作用的新系统和有效测试新疗法的新系统。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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David K Ann其他文献
The role of tyrosine kinase Etk/Bmx in EGF-induced apoptosis of MDA-MB-468 breast cancer cells
酪氨酸激酶 Etk/Bmx 在表皮生长因子诱导的 MDA-MB-468 乳腺癌细胞凋亡中的作用
- DOI:
10.1038/sj.onc.1207308 - 发表时间:
2003-12-15 - 期刊:
- 影响因子:7.300
- 作者:
Kai-Yun Chen;Li-Ming Huang;Hsing-Jien Kung;David K Ann;Hsiu-Ming Shih - 通讯作者:
Hsiu-Ming Shih
David K Ann的其他文献
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{{ truncateString('David K Ann', 18)}}的其他基金
Fatty acids and their receptors-mediated tumor metastasis and progression
脂肪酸及其受体介导的肿瘤转移和进展
- 批准号:
10330011 - 财政年份:2020
- 资助金额:
$ 21.63万 - 项目类别:
Fatty acids and their receptors-mediated tumor metastasis and progression
脂肪酸及其受体介导的肿瘤转移和进展
- 批准号:
9916932 - 财政年份:2020
- 资助金额:
$ 21.63万 - 项目类别:
Fatty acids and their receptors-mediated tumor metastasis and progression
脂肪酸及其受体介导的肿瘤转移和进展
- 批准号:
10549362 - 财政年份:2020
- 资助金额:
$ 21.63万 - 项目类别:
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