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.

项目摘要/摘要 肥胖与绝经后雌激素受体阳性（ER+）乳腺癌（BC）有关 所有BC亚型的死亡率增加2-4倍。对治疗耐药性的机制 并确保肥胖症中致命的BC转移尚不清楚。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，雌激素（E1），肥胖，共同的雌激素（E1）如何高3倍 使用NFκB和晚期糖基化终产物（RAGE）的受体进行操作，以更新转移。 我们的数据表明BC细胞：脂肪细胞接触激活NFκB，E1：ERα诱导促炎性 两种细胞类型中的细胞因子基因，刺激更大的癌症干细胞的扩张以及快速的ER+ BC生长和 转移。初步数据显示NFκB和E1：ER共同刺激编码愤怒配体的基因（S100A8/A9）。 RAGE是其他细胞类型（包括免疫和内皮细胞）中的主要NFκB激活剂，但鲜为人知 BC中的愤怒/NFκB信号传导。我们表明愤怒在肿瘤细胞和宿主微环境中都作用 （基质和脂肪）上调募集髓样衍生抑制细胞（MDSC）的细胞因子以促进 转移。在肥胖小鼠中，E1通过刺激免疫驱虫来增加BC的生长。新数据显示 抗雌激素的ER+BC系，包括轴承ESR1突变，显示NFκB活性增加和 愤怒水平。此外，研究性愤怒抑制剂TTP488与Er-Blocker，Fulvertant合作， 在多种耐药线中阻止耐抗雌激素的ER+ BC细胞生长。在这里，我们测试E1结合的ER， NFκB和愤怒在ER+ BC，脂肪细胞和免疫核管中相互作用，以驱动内分泌疗法的基因程序 电阻，如果愤怒的抑制剂扭转了这一点。 我们假设E1：ER和NFκB合作引起愤怒，愤怒激活了NFκB，在ER+ BC中 肿瘤细胞和肿瘤脂肪以驱动肿瘤的促炎性促炎性基因表达程序 进展和获得的耐药性。 AIM 1将识别肿瘤细胞内部馈送机制 在富含E1的乳腺癌环境中介导愤怒/NFκB激活，测试E1和NFκB是否引起愤怒 激活Rac1和TLR4在ER+ BC中驱动前馈发育型NFκB激活。 AIM 2将测试是否愤怒 在乳腺癌细胞中介导E1/ER和NFκB的促疾病，促炎靶基因激活。我们 将识别E1/ER和NFκBcistromes和转录组，并测试是否需要愤怒。相关性 肥胖中的rage依赖性ER/κB共靶基因激活将通过比较中的scrnaseq验证 肥胖和精益供体的人类ER+乳腺癌。 AIM 3将识别肿瘤细胞 - 超支机制 因此，肥胖中的肿瘤脂肪宿主促进了ER+中获得的抗雌激素耐药性和免疫进化 癌症。 AIM 4将测试rage抑制剂是否恢复了器官和PDX模型中的内分泌治疗反应 源自ER+乳腺癌。这项工作可以确定治疗获得的内分泌的新方法 转移性ER+BC的耐药性，特别是肥胖患者。