Targeting RAGE in tumor and TME to oppose inflammation and drug resistance in obesity associated ER+ breast cancer
靶向肿瘤和 TME 中的 RAGE,对抗肥胖相关 ER 乳腺癌的炎症和耐药性
基本信息
- 批准号:10734834
- 负责人:
- 金额:$ 51.65万
- 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:2023-07-07 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:AdipocytesAmericanAutomobile DrivingBindingBiological AssayBreast Cancer CellBreast Cancer PatientBreast Cancer Risk FactorBreast Cancer therapyBreast cancer metastasisCCL2 geneCancer Cell GrowthCancer PatientCellsCessation of lifeCytokine GeneDataDiseaseDrug resistanceESR1 geneEndocrineEndothelial CellsEnvironmentEstrogen AntagonistsEstrogen Receptor alphaEstrogen receptor positiveEstrogensEstroneFatty acid glycerol estersFulvestrantFutureGene ActivationGene ExpressionGenesGoalsGrowthHumanIL6 geneImmuneImmune EvasionImmunologic StimulationImpairmentIn VitroInfiltrationInflammationInflammatoryLife StyleLigandsMCF7 cellMalignant NeoplasmsMediatingMediatorModelingMusMutationMyeloid-derived suppressor cellsNeoplasm MetastasisObese MiceObesityOncogenicOrganoidsOutcomePharmacotherapyPostmenopausePremenopausePreventable cancer causeRepressionResistanceResponse ElementsRiskS100A8 geneSignal TransductionTLR4 geneTestingTherapeuticThinnessTumor ImmunityWorkacquired drug resistancecancer stem cellcancer subtypescell typechemokineclinical investigationcomorbiditycytokinediet-induced obesityeffective therapygene inductionhormone therapyimmunoregulationin vivoinhibitorinhibitor therapymalignant breast neoplasmmammarymortalitymouse modelmutantneoplastic cellnovel strategiesobese patientsobesity treatmentpatient derived xenograft modelpreclinical studyprogramsreceptor for advanced glycation endproductsrecruitresponsesingle-cell RNA sequencingstem cell expansionsynergismtherapy resistanttranscription factortranscriptometranscriptomicstreatment responsetumortumor microenvironmenttumor progressionweight loss intervention
项目摘要
PROJECT SUMMARY/ABSTRACT
Obesity is associated with increased postmenopausal estrogen receptor-positive (ER+) breast cancer (BC)
risk and a 2-4 fold increase in mortality from all BC subtypes. Mechanisms of increased resistance to therapy
and ensuing fatal BC metastasis in obesity remain unclear. Here, we study how the inflammatory state of obesity
drives ER+ BC. We study how postmenopausal estrogen, estrone (E1), which is 3-fold higher in obesity, co-
operates with NFκB and the Receptor for Advanced Glycation End-products (RAGE) to upregulate metastasis.
Our data indicate that BC cell:adipocyte contact activates NFκB and E1:ERα to induce pro-inflammatory
cytokine genes in both cell types, stimulating greater cancer stem cell expansion, and rapid ER+ BC growth and
metastasis. Preliminary data show NFκB and E1:ER co-stimulate genes encoding RAGE-ligands (S100A8/A9).
RAGE is a major NFκB activator in other cell types (including immune and endothelial cells), but little is known
of RAGE/NFκB signaling in BC. We showed that RAGE acts in both tumor cells and the host microenvironment
(stroma and fat) to upregulate cytokines that recruit myeloid-derived suppressor cells (MDSC) to promote
metastasis. In obese mice, E1 increases BC growth, in part by stimulating immune evasion. New data show
antiestrogen-resistant ER+BC lines, including those bearing ESR1 mutations, show increased NFκB activity and
RAGE levels. Moreover, the investigational RAGE inhibitor, TTP488, cooperates with the ER-blocker, fulvestrant,
to arrest antiestrogen-resistant ER+ BC cell growth in multiple resistant lines. Here, we test if E1-bound ER,
NFκB, and RAGE interact in ER+ BC, adipocytes and immune cells to drive gene programs of endocrine therapy
resistance and if RAGE inhibitors reverse this.
We hypothesize that E1:ER and NFκB cooperate to induce RAGE, and RAGE activates NFκB in ER+ BC
tumor cells and peritumoral fat to drive pro-inflammatory, pro-metastatic gene expression programs of tumor
progression and acquired drug resistance. Aim 1 will identify tumor cell-intrinsic feed-forward mechanisms
mediating RAGE/ NFκB activation in an E1-rich breast cancer environment, testing if E1 and NFκB induce RAGE
to activate Rac1, and TLR4 driving feed-forward oncogenic NFκB activation in ER+ BC. Aim 2 will test if RAGE
mediates pro-oncogenic, pro-inflammatory target gene activation by E1/ER and NFκB in breast cancer cells. We
will identify E1/ER and NFκB cistromes and transcriptomes and test if these require RAGE. The relevance of
RAGE-dependent ER/κB co-target genes activation in obesity will be validated by comparing ScRNAseq in
human ER+ breast cancers from obese and lean donors. Aim 3 will identify tumor cell-extrinsic mechanisms
whereby peritumoral fat in obese hosts promotes acquired antiestrogen resistance and immune evasion in ER+
cancers. Aim 4 will test if RAGE inhibitors restore endocrine therapy responses in organoid and PDX models
derived from ER+ breast cancers. This work could identify new approaches to treating acquired endocrine
resistance in metastatic ER+BC, particularly in obese patients.
项目总结/文摘
项目成果
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