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/摘要
肥胖与绝经后雌激素受体阳性(ER+)乳腺癌(BC)增加有关
所有BC亚型的死亡率增加2-4倍。对治疗耐药性增加的机制
以及随之而来的肥胖致死性BC转移仍不清楚。在这里,我们研究肥胖的炎症状态
驱动ER+ BC。我们研究了绝经后雌激素,雌酮(E1),这是3倍高肥胖,
与NFκB和晚期糖基化终产物受体(Receptor for Advanced Glycation End-products,ERK)一起作用,上调转移。
我们的数据表明,BC细胞与脂肪细胞接触激活NFκB和E1:ERα,诱导促炎性细胞因子的产生。
两种细胞类型中的细胞因子基因,刺激更大的癌症干细胞扩增和快速ER+ BC生长,
转移初步数据显示NFκB和E1:ER共刺激编码RAGE配体(S100 A8/A9)的基因。
在其他细胞类型(包括免疫细胞和内皮细胞)中,NF κ B是一种主要的NFκB激活剂,但目前知之甚少
B/NFκB信号通路的变化。我们发现,在肿瘤细胞和宿主微环境中,
(基质和脂肪)上调细胞因子,细胞因子招募髓源性抑制细胞(MDSC),
转移在肥胖小鼠中,E1部分通过刺激免疫逃避来增加BC生长。新数据显示
抗雌激素抗性ER+BC系,包括携带ESR 1突变的那些,显示NFκB活性增加,
水平线。此外,研究中的ER抑制剂TTP 488与ER阻断剂氟维司群协同作用,
以阻止抗雌激素抗性ER+ BC细胞在多种抗性系中的生长。在这里,我们测试是否E1结合ER,
NFκB和NF κ B在ER+ BC、脂肪细胞和免疫细胞中相互作用,以驱动内分泌治疗的基因程序
抵抗力,如果抑制剂逆转这一点。
我们推测E1:ER和NFκB B协同诱导E1:BC,而E1:ER+ BC中NFκB B活化
肿瘤细胞和瘤周脂肪来驱动肿瘤的促炎、促转移基因表达程序
进展和获得性耐药性。目标1将确定肿瘤细胞内在的前馈机制
在富含E1的乳腺癌环境中介导NFκB/ NF B活化,测试E1和NFκB是否诱导E1/ NFκ B活化,
激活Rac 1和TLR 4,驱动ER+ BC中的前馈致癌NFκB激活。目标2将测试是否存在
在乳腺癌细胞中通过E1/ER和NFκB介导促癌、促炎靶基因活化。我们
将鉴定E1/ER和NFκB顺式组和转录组,并检测这些是否需要测序。的相关性
肥胖症中RAGE依赖性ER/κB共靶基因的激活将通过比较ScRNAseq与
来自肥胖和瘦弱捐赠者的人类ER+乳腺癌。目标3将确定肿瘤细胞的外在机制
由此肥胖宿主的瘤周脂肪促进ER+中的获得性抗雌激素抗性和免疫逃避。
癌的目的4将测试在类器官和PDX模型中,β-内酰胺酶抑制剂是否能恢复内分泌治疗反应
来源于ER+乳腺癌。这项工作可以确定治疗获得性内分泌的新方法
在转移性ER+BC中,特别是在肥胖患者中,
项目成果
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