Role of hypoxia in fibroblast reprogramming in pancreatic cancer
缺氧在胰腺癌成纤维细胞重编程中的作用
基本信息
- 批准号:10748608
- 负责人:
- 金额:$ 4.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAccountingAreaBlood VesselsCancer ControlCellsCoculture TechniquesDataDesmoplasticDiagnosisDiseaseExtracellular MatrixFibroblastsGoalsHumanHypoxiaHypoxia Inducible FactorImmuneIncidenceInflammatoryInterleukin-1Knock-outLinkM cellMalignant NeoplasmsMalignant neoplasm of pancreasMediatingMediatorMolecularMusMutationOxygenPancreatic Ductal AdenocarcinomaPathway interactionsPatientsPlayProductionProteinsRegulationResistanceRoleSamplingSignal PathwaySignal TransductionStromal CellsSystemTestingTherapeuticTissuesWitWorkcancer cellcancer therapycytokinedensitydesigngenetic signaturehypoxia inducible factor 1in vivoinsightmortalitymouse modelneoplastic cellnormoxianovel therapeutic interventionpancreatic cancer cellspancreatic tumorigenesisresponsesingle-cell RNA sequencingtherapy resistanttumortumor hypoxiatumor initiationtumor microenvironmenttumorigenesis
项目摘要
PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDAC) is a prevalent form of pancreatic cancer, accounting for about 90%
of all cases of this disease. PDAC is highly fatal, where mortality closely parallels incidence, primarily due to the
inability to diagnose PDAC at early stages and resistance to all existing treatments. Besides genetic changes in
tumor cells, the tumor microenvironment plays a key role in tumor initiation, progression, and therapeutic
resistance. PDAC is notable for its dense desmoplastic stroma, consisting of extracellular matrix, cancer-
associated fibroblasts (CAFs), and immune cells. Another notable feature of the PDAC microenvironment is
hypoxia, a condition of insufficient oxygen availability. Although hypoxia leads to adaptive responses in both
cancer cells and stromal cells, the effects of hypoxia and hypoxia-inducible factor 1ɑ (HIF1ɑ), a master regulator
of hypoxic adaptation, on the PDAC stroma and tumor-stroma interactions are not fully understood. We have
recently found that inflammatory CAFs (iCAFs), a CAF subset producing high levels of inflammatory cytokines,
are linked to the hypoxia-related gene signature and the HIF1 signaling pathway in human and mouse PDAC.
By exposing 3D cocultures of pancreatic tumor cells and fibroblasts to either hypoxia or normoxia, we
demonstrated that hypoxia promotes iCAF formation via IL1ɑ secreted from tumor cells. Importantly, the
presence of hypoxic fibroblasts further elevated IL1ɑ levels in tumor cells, implicating hypoxia as a modulator of
bidirectional interactions between tumor cells and fibroblasts. Based on these data, I hypothesize that hypoxia
promotes iCAF formation by modulating bidirectional interactions between tumor cells and fibroblasts in PDAC.
In Specific Aim 1, I will determine how hypoxia induces IL1ɑ expression in tumor cells via fibroblasts by using a
three-dimensional (3D) coculture system of pancreatic tumor cells and fibroblasts and exposing the coculture to
either hypoxia or normoxia. In Specific Aim 2, I will determine whether and how fibroblast HIF1ɑ regulates tumor
cell-fibroblast interactions and pancreatic tumorigenesis by using 3D cocultures of tumor cells and fibroblasts
deficient of HIF1ɑ, and using mouse models lacking fibroblast expression of HIF1ɑ. My work will identify the
molecular mechanisms underlying hypoxic regulation of cancer cell-CAF crosstalk. In addition, my studies will
determine how activation of HIF1ɑ within CAFs regulates the tumor stroma and PDAC progression, which will
inform targeting fibroblast HIF1ɑ as a potential therapeutic avenue to treat PDAC patients.
项目总结
项目成果
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