PDGF-BB and the metastatic brain microenvironment
PDGF-BB和转移性脑微环境
基本信息
- 批准号:10718597
- 负责人:
- 金额:$ 48.75万
- 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:2023-08-11 至 2028-07-31
- 项目状态:未结题
- 来源:
- 关键词:ANGPT1 geneAblationAngiogenic FactorAngiopoietinsAstrocytesBiologyBlood - brain barrier anatomyBlood VesselsBrainBrain NeoplasmsBreast Cancer CellBreast Cancer PatientBreast Epithelial CellsBreast cancer metastasisCellsCoculture TechniquesCollaborationsComplexCytometryDataDiagnosisDistantEvaluationFibroblastsHumanHyperactivityImmune EvasionIn VitroInjectionsIntracranial NeoplasmsInvestigationKnowledgeLigandsMalignant - descriptorMammary NeoplasmsMediatingMesenchymalMetastatic malignant neoplasm to brainMicrofluidicsMicrogliaMolecularMusMyelogenousMyeloid CellsNeoplasm MetastasisOrganPDGFRB genePatientsPericytesPhagocytesPhenotypePlatelet-Derived Growth FactorPlatelet-Derived Growth Factor ReceptorPlatelet-Derived Growth Factor beta ReceptorPopulationPublishingSignal TransductionSiteSurvival RateTestingTreatment EfficacyTumor PromotionWomanWorkautocrineblood-brain barrier permeabilizationbrain remodelingcancer diagnosiscerebral microvasculatureclinically relevantexperimental studyimmunoregulationin vivoinhibitormalignant breast neoplasmmortalitymouse modelneoplastic cellnovelplatelet-derived growth factor BBprognosticreceptorresponsesmall moleculesmall molecule inhibitortargeted treatmenttherapeutic evaluationtumortumor growthtumor microenvironmenttumor-immune system interactionstumorigenic
项目摘要
PROJECT SUMMARY
Recent studies by my group have highlighted the clinical relevance of platelet-derived growth factor-B
(PDGFB) secreted by malignant breast epithelial cells and its receptor, platelet-derived growth factor receptor
beta (PDGFRβ), expressed on cells of the mesenchymal lineage (e.g., fibroblasts, pericytes, astrocytes) in the
promotion of breast cancer metastasis to the brain (BCBM). Our studies revealed: (1) PDGFB ligand promotes
primary and intracranial breast tumor growth, (2) mesenchymal-specific PDGFRβ hyperactivity (Fsp1-
cre;PdgfrbD849V/+) promotes BCBM in mice, (3) PDGFB ligand expression in the primary breast tumor is
prognostic of brain metastases in human breast cancer patients, and (4) inhibition with a small molecule
selective PDGFR inhibitor (crenolanib) reduces intracranial tumor growth in mouse models of BCBM. This
published work discovered PDGFB-to-PDGFRβ signaling as a clinically relevant signaling node for predicting,
and potentially treating, BCBM. Our continued investigation into how breast cancer-derived PDGFB
mechanistically modulates the brain TME has further revealed previously unknown immuno-modulatory and
vascular effects. The current application will directly test the overarching hypothesis that breast cancer cells
expressing PDGFB completely transform the brain metastatic niche, both by creating a pro-tumorigenic
immune microenvironment and by invoking vascular changes. In Aim 1, the interaction between breast cancer
cells with/without PDGFB and the brain immune microenvironment will be evaluated in vitro (microglial co-
cultures and conditioned media experiments) and in vivo (intracardiac injections followed by brain
histopathological evaluation and high-plex spectral cytometry). This aim will also evaluate if PDGFB causes
changes in the microglial phagocytic response as well as shifts in anti-tumorigenic/pro-tumorigenic myeloid cell
phenotypes. These studies will be the first to directly test whether breast cancer-derived PDGFB drives
immune evasion in the brain metastatic microenvironment. In Aim 2, the interaction between breast cancer
cells with/without PDGFB and the brain microvasculature will be evaluated in vitro (BBB spheroids,
microfluidics) and in vivo (intracardiac injections followed by brain histopathological evaluation). This aim will
also evaluate a putative mechanism by which PDGFB functions in an autocrine manner to upregulate the pro-
angiogenic factor Angiopoietin-1, and whether these vascular changes can be ablated with small molecule
inhibitors of PDGFRβ and/or Tie2 (angiopoietin receptor). These studies will be the first to directly test the
hypothesis that breast cancer-derived PDGFB alters the brain microvasculature indirectly through an autocrine
PDGFB-PDGFRβ-Ang1 axis. Upon completion of the proposed study, we will have determined potentially
targetable mechanism(s) by which PDGFB pre-conditions the brain microenvironment allowing for metastasis
to this site.
项目总结
项目成果
期刊论文数量(0)
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