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

• 批准号: 10734834
• 负责人: Barry Ian Hudson
• 金额: $ 51.65万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10734834
• 关键词: Adipocytes; American; Automobile Driving; Binding; Biological Assay; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer therapy; Breast cancer metastasis; CCL2 gene; Cancer Cell Growth; Cancer Patient; Cells; Cessation of life; Cytokine Gene; Data; Disease; Drug resistance; ESR1 gene; Endocrine; Endothelial Cells; Environment; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen receptor positive; Estrogens; Estrone; Fatty acid glycerol esters; Fulvestrant; Future; Gene Activation; Gene Expression; Genes; Goals; Growth; Human; IL6 gene; Immune; Immune Evasion; Immunologic Stimulation; Impairment; In Vitro; Infiltration; Inflammation; Inflammatory; Life Style; Ligands; MCF7 cell; Malignant Neoplasms; Mediating; Mediator; Modeling; Mus; Mutation; Myeloid-derived suppressor cells; Neoplasm Metastasis; Obese Mice; Obesity; Oncogenic; Organoids; Outcome; Pharmacotherapy; Postmenopause; Premenopause; Preventable cancer cause; Repression; Resistance; Response Elements; Risk; S100A8 gene; Signal Transduction; TLR4 gene; Testing; Therapeutic; Thinness; Tumor Immunity; Work; acquired drug resistance; cancer stem cell; cancer subtypes; cell type; chemokine; clinical investigation; comorbidity; cytokine; diet-induced obesity; effective therapy; gene induction; hormone therapy; immunoregulation; in vivo; inhibitor; inhibitor therapy; malignant breast neoplasm; mammary; mortality; mouse model; mutant; neoplastic cell; novel strategies; obese patients; obesity treatment; patient derived xenograft model; preclinical study; programs; receptor for advanced glycation endproducts; recruit; response; single-cell RNA sequencing; stem cell expansion; synergism; therapy resistant; transcription factor; transcriptome; transcriptomics; treatment response; tumor; tumor microenvironment; tumor progression; weight loss intervention

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.

项目概要/摘要 肥胖与绝经后雌激素受体阳性 (ER+) 乳腺癌 (BC) 的增加有关 所有 BC 亚型的风险和死亡率增加 2-4 倍 治疗耐药性增加的机制。 肥胖导致的致命 BC 转移仍不清楚。在此，我们研究肥胖的炎症状态是如何发生的。 我们研究了绝经后雌激素、雌酮 (E1)（在肥胖症中含量高出 3 倍）如何共同促进 ER+ BC。 与 NFκB 和高级糖基化终产物受体 (RAGE) 一起作用以上调转移。 我们的数据表明 BC 细胞:脂肪细胞接触激活 NFκB 和 E1:ERα 诱导促炎 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，以及快速 ER+ BC 生长和 初步数据显示 NFκB 和 E1:ER 共同刺激编码 RAGE 配体 (S100A8/A9) 的基因。 RAGE 是其他细胞类型（包括免疫细胞和内皮细胞）中的主要 NFκB 激活剂，但人们知之甚少 我们发现 RAGE 在肿瘤细胞和宿主微环境中都有作用。 （基质和脂肪）上调细胞因子，招募骨髓源性抑制细胞（MDSC）以促进 新数据显示，在肥胖小鼠中，E1 可以部分通过刺激免疫逃避来促进 BC 生长。 抗雌激素耐药的 ER+BC 系，包括那些带有 ESR1 突变的系，显示出 NFκB 活性增加，并且 此外，研究中的 RAGE 抑制剂 TTP488 与 ER 阻滞剂氟维司群协同作用。 阻止多个抗性细胞系中抗雌激素抗性 ER+ BC 细胞的生长 在这里，我们测试 E1 结合的 ER， NFκB 和 RAGE 在 ER+ BC、脂肪细胞和免疫细胞中相互作用，驱动内分泌治疗的基因程序 耐药性以及 RAGE 抑制剂是否能逆转这一情况。 我们追寻E1:ER和NFκB协同诱导RAGE，并且RAGE在ER+BC中激活NFκB 肿瘤细胞和瘤周脂肪驱动肿瘤的促炎、促转移基因表达程序 目标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 RAGE/NFκB 激活，测试 E1 和 NFκB 是否诱导 RAGE 激活 Rac1 和 TLR4，在 ER+ BC 中驱动前馈致癌 NFκB 激活，Aim 2 将测试 RAGE 是否有效。 在乳腺癌细胞中通过 E1/ER 和 NFκB 介导促癌、促炎靶基因激活。 将识别 E1/ER 和 NFκB 顺反子和转录组，并测试这些是否需要 RAGE 的相关性。 将通过比较 ScRNAseq 来验证肥胖中 RAGE 依赖性 ER/κB 共靶基因的激活 来自肥胖和瘦捐献者的人类 ER+ 乳腺癌的目标 3 将确定肿瘤细胞的外在机制。 因此，肥胖宿主的瘤周脂肪促进 ER+ 获得性抗激素抵抗和免疫逃避 目标 4 将测试 RAGE 抑制剂是否能恢复类器官和 PDX 模型中的内分泌治疗反应。 源自 ER+ 乳腺癌的这项工作可以确定治疗获得性内分泌的新方法。 转移性 ER+BC 耐药，尤其是肥胖患者。