Role of WNT-EGFR crosstalk by EVs and exomeres in normal colon and colon cancer
Role of WNT-EGFR crosstalk by EVs and exomeres in normal colon and colon cancer
批准号:
10544807
负责人:
Robert J. Coffey
金额:
$34.57万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-01-22 至 2024-12-31
关键词:
AREG geneAppleAutomobile DrivingBiogenesisCell LineCellsCetuximabColonColon CarcinomaColonic NeoplasmsColorectal CancerDataDrug resistanceEGF geneEpidermal Growth Factor ReceptorEpitheliumEquilibriumFluorescenceGenesGoalsHomeostasisHumanIntestinesKRAS2 geneLGR5 geneLacZ GenesLarge Intestine CarcinomaLinkLuciferasesMDCK cellMalignant NeoplasmsMediatingMethodologyModelingMusMutationNeoplasmsNeoplastic Cell TransformationOncogenicOrganoidsPathway interactionsPatientsPatternPlayPopulationPreparationProteinsPublishingRNAReagentRegulationReporterReportingResistanceRoleSignal PathwaySignal TransductionSortingTestingTextTumor-Associated ProcessVesicleWNT Signaling PathwayWorkcolorectal cancer progressionexperimental studyextracellular vesiclesintestinal cryptmouse modelmutantnanoparticleneoplasticoverexpressionstem cell functionstem cell nichestem cellstumortumor growthtumor progressionvesicular release
中文摘要
项目3总结(科菲)
英文摘要
Project 3 Summary (Coffey)
The Coffey lab has identified important links between WNT and EGFR signaling in cetuximab (CTX) resistance
and intestinal crypt homeostasis. We recently reported a new mode of CTX resistance due to increased WNT
signaling mediated by miR-100/-125b. These two miRs are upregulated in extracellular vesicles (EVs) released
by CTX-resistant cells and these EVs can transfer CTX resistance. In a unique EGFR and WNT reporter mouse
model, we show that activation of WNT signaling in an EGFR-sensitized background dramatically increases both
EGFR and non-cell autonomous WNT activity. Based on these findings, we propose a model of opposing
gradients of EGFR and WNT activity in the colonic stem cell niche (SCN) that contribute to homeostasis and
disruption of the gradient is a feature of neoplastic transformation. We hypothesize that in the normal crypt niche
EVs and exomeres released by the EGFR-active and WNT-active compartments reinforce the EGFR-WNT
gradient and in CRC these nanoparticles serve to drive tumor growth and define cancer progression due to their
oncogenically altered constituents. The model also provides a framework to further examine the role of EVs and
exomeres in conferring CTX resistance, at least in part, via increased WNT signaling. To examine this model
and to determine how EVs participate in CTX resistance, with the ultimate goal of devising strategies to overcome
CTX resistance, we propose three Aims. Aim 1 is to determine the effect of EVs and exomeres isolated from
highly informative paired cell lines on EGFR and WNT activity in reporter cell lines. Aim 2 is to test the hypothesis
that these EVs and exomeres regulate normal stem cell patterning and tumor progression using our unique
EGFR and WNT reporter mouse models and their derived organoids. Aim 3 is to elucidate mechanistic
underpinnings of EV participation in resistance to EGFR blockade. This work has the potential to alter our
fundamental understanding of normal stem cell function, regulation of tumor growth and processes regulating
drug resistance.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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批准号:10820067
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依托单位:
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Shaping the Microenvironment by DPEP1 Facilitates Adenoma Progression
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资助金额:$11.27万
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财政年份:2022
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依托单位:
Shaping the Microenvironment by DPEP1 Facilitates Adenoma Progression
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批准号:10697369
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项目类别:
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资助金额:$37.95万
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财政年份:2022
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负责人:Robert J. Coffey
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依托单位:
Administrative Core
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批准号:10218105
-
项目类别:
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资助金额:$18.3万
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财政年份:2019
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负责人:Robert J. Coffey
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依托单位:
Project 1: Interrogating Distinct Tumor-Initiating Cells in CRC
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批准号:10700848
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资助金额:$38.94万
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依托单位:
Distribution of Molecular Features for Colorectal Cancers in Northern Tanzania
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批准号:10845027
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项目类别:
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资助金额:$12.5万
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财政年份:2019
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负责人:Robert J. Coffey
-
依托单位:
Administrative Core
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批准号:10912861
-
项目类别:
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资助金额:$12.5万
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财政年份:2019
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负责人:Robert J. Coffey
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依托单位:
Vanderbilt-Ingram Cancer Center SPORE in Gastrointestinal Cancer
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批准号:9975125
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项目类别:
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资助金额:$237.91万
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财政年份:2019
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负责人:Robert J. Coffey
-
依托单位:
Administrative Core
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批准号:10700838
-
项目类别:
-
资助金额:$18.83万
-
财政年份:2019
-
负责人:Robert J. Coffey
-
依托单位:
Vanderbilt-Ingram Cancer Center SPORE in Gastrointestinal Cancer
-
批准号:10443606
-
项目类别:
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资助金额:$228.76万
-
财政年份:2019
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负责人:Robert J. Coffey
-
依托单位:
Administrative Core
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批准号:10443607
-
项目类别:
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资助金额:$18.83万
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财政年份:2019
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负责人:Robert J. Coffey
-
依托单位:
Project 1: Interrogating Distinct Tumor-Initiating Cells in CRC
-
批准号:10443612
-
项目类别:
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资助金额:$38.94万
-
财政年份:2019
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负责人:Robert J. Coffey
-
依托单位:
Vanderbilt-Ingram Cancer Center SPORE in Gastrointestinal Cancer
-
批准号:10218104
-
项目类别:
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资助金额:$227.7万
-
财政年份:2019
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负责人:Robert J. Coffey
-
依托单位:
Vanderbilt-Ingram Cancer Center SPORE in Gastrointestinal Cancer
-
批准号:10700836
-
项目类别:
-
资助金额:$227.89万
-
财政年份:2019
-
负责人:Robert J. Coffey
-
依托单位:
Project 1: Interrogating Distinct Tumor-Initiating Cells in CRC
-
批准号:10218109
-
项目类别:
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资助金额:$39.92万
-
财政年份:2019
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负责人:Robert J. Coffey
-
依托单位:
Integrative Single-Cell Atlas of Host and Microenvironment in Colorectal Neoplastic Transformation
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批准号:10380489
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项目类别:
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资助金额:$21.18万
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财政年份:2018
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负责人:Robert J. Coffey
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依托单位:
Functional changes in secreted RNA biogenesis using in vivo colon tumor models
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批准号:9331322
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项目类别:
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资助金额:$43.49万
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财政年份:2017
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负责人:Robert J. Coffey
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依托单位:
Integrated approach to study early and late events in colonic neoplasia: mouse to man
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批准号:10589898
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项目类别:
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资助金额:$91.58万
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财政年份:2017
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负责人:Robert J. Coffey
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依托单位:
国内基金
海外基金
苹果茎沟病毒(Apple stem grooving virus, ASGV)CP基因介导的RNAi 转基因对ASGV侵染和脱毒的影响研究
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批准号:31801709
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项目类别:青年科学基金项目
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资助金额:21.0万元
-
批准年份:2018
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负责人:冯超红
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依托单位: