Mechanisms of myeloid cell driven pancreatic plasticity and carcinogenesis
Mechanisms of myeloid cell driven pancreatic plasticity and carcinogenesis
批准号:
10607213
负责人:
Timothy Louis Frankel
金额:
$63.67万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-02-01 至 2028-01-31
关键词:
AccelerationAcinar CellArchitectureAutopsyCCR1 geneCancer EtiologyCell SeparationCellsCessation of lifeCytokine ReceptorsDataDependenceDevelopmentDiphtheria ToxinDiseaseDisease modelDuct (organ) structureElementsEpithelial CellsEpitheliumEvolutionExcisionExposure toFibroblastsGenesGenetically Engineered MouseGoalsHumanImmuneImpairmentIn VitroIndolentInflammationKRAS oncogenesisKRAS2 geneKnowledgeLeadLesionLinkMAP Kinase GeneMacrophageMaintenanceMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of pancreasMapsMediatingMusMutationMyeloid CellsNeoplastic Cell TransformationNon-MalignantOncogenicOperative Surgical ProceduresOrgan DonationsOrgan DonorOrganoidsPancreasPancreatic AdenocarcinomaPancreatic Intraepithelial NeoplasiaPancreatitisPathway interactionsPatientsPenetrancePopulationPredispositionPreneoplastic ConditionsProcessProliferatingPublishingRecurrenceReproducibilityResidual stateRiskRoleSamplingSchemeSignal TransductionSystemT-Cell ActivationT-LymphocyteTestingTissuesTumor MarkersTumor PromotionUnited Statesadvanced diseaseanti-tumor immune responsecancer cellcancer invasivenesscarcinogenesiscell dedifferentiationcell preparationchronic pancreatitisfunctional statusgenetic approachgranulocytehigh riskhigh risk populationhuman tissueimmune cell infiltratein silicoin vivomouse modelmutantneoplasticneoplastic cellnew combination therapiesnovel strategiespancreatic cancer modelpancreatic tumorigenesispharmacologicpolarized cellpreventprogenitorprogramstherapeutic developmenttissue repairtumortumor growthtumor initiationtumor microenvironmenttumor progressiontumorigenesistumorigenic
中文摘要
摘要
英文摘要
Abstract
Pancreatic cancer is almost invariably associated with the presence of an oncogenic, hyper-activated form
of the KRAS gene. Oncogenic KRAS mutations are present in most human Pancreatic Intraepithelial
Neoplasia (PanIN). Expression of oncogenic Kras in the pancreas epithelium of genetically engineered
mouse models (GEMM) mimics human carcinogenesis, and provides a system to study early stages of the
disease within the context of an intact microenvironment. The onset of pancreatic carcinogenesis requires
dedifferentiation of epithelial cells to a duct-like, progenitor-like cell that is susceptible to oncogenic
transformation. During this process, and throughout the progression of PanIN and cancer, the
microenvironment surrounding the lesions is reprogrammed by tumor cells and, in turn, promotes
carcinogenesis. Among the most abundant components of the PanIN and pancreatic cancer
microenvironment are myeloid cells, including macrophages, granulocytes and several populations of
immature myeloid cells. We have previously shown that myeloid cells are required for the onset of
carcinogenesis, as they promote acinar cell dedifferentiation and sustained proliferation of early lesions.
Further, in advanced disease, myeloid cells inhibit T cell mediated anti-tumor immune responses.
However, myeloid cells can have the opposite effect, promoting tissue repair and remodeling rather than
carcinogenesis. The goal of this proposal is to investigate the crosstalk between tumor cells and myeloid
cells during the onset, progression and maintenance of pancreatic carcinogenesis. Using a combination
of human patient samples and genetically engineered mouse models, as well as in vivo, in vitro and in
silico approaches, we propose to map myeloid cell populations and functional status in the healthy
pancreas, in PanIN, and in pancreatic cancer in human and mouse (Aim 1); define the function of myeloid
cells at different stages of carcinogenesis (Aim 2); and reprogram myeloid cells to prevent/treat pancreatic
cancer (Aim 3). Together these aims will advance our understanding of key cellular interactions that
regulate pancreas carcinogenesis, and identify and test new combination therapy approaches for this
disease.
期刊论文(0)
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科研奖励(0)
会议论文
Role of environmental toxins in shaping the tumor immune microenvironment
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批准号:10366833
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项目类别:
-
资助金额:$0.0万
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财政年份:2022
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负责人:Timothy Louis Frankel
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依托单位:
Role of environmental toxins in shaping the tumor immune microenvironment
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批准号:10644980
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项目类别:
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资助金额:$0.0万
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财政年份:2022
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负责人:Timothy Louis Frankel
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依托单位:
Epithelial-immune cell crosstalk during injury and recovery in acute pancreatitis
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批准号:10363904
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项目类别:
-
资助金额:$44.68万
-
财政年份:2021
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负责人:Timothy Louis Frankel
-
依托单位:
Epithelial-immune cell crosstalk during injury and recovery in acute pancreatitis
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批准号:10543109
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项目类别:
-
资助金额:$44.68万
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财政年份:2021
-
负责人:Timothy Louis Frankel
-
依托单位:
Role of Interleukin-22 and Innate Lymphoid Cells in Pancreas Cancer Initiation and Progression
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批准号:9313852
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项目类别:
-
资助金额:$10.61万
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财政年份:2016
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负责人:Timothy Louis Frankel
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依托单位:
海外基金