Beige Adipocytes and African American Breast Tumors

米色脂肪细胞和非裔美国人乳腺肿瘤

• 批准号: 10202503
• 负责人: SHEHLA PERVIN
• 金额: $ 35.88万
• 依托单位: CHARLES R. DREW UNIVERSITY OF MED & SCI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-06 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202503
• 关键词: Adipocytes; Adipose tissue; African American; Aggressive behavior; Biological Process; Breast Cancer Cell; Breast Cancer cell line; Cells; Characteristics; Clinical; Coculture Techniques; Data; Development; Genetic; Growth; Human; IL-13Ralpha1; IL4 gene; Immunofluorescence Immunologic; Incidence; Infiltration; Interleukin-10; Interleukin-13; Mammary Neoplasms; Molecular; Mus; Nature; Outcome; Patients; Pharmacology; Phenotype; Platelet-Derived Growth Factor alpha Receptor; Population; Property; Publishing; Regulation; Reporting; Role; Testing; Therapeutic Intervention; Time; Tissues; Tyrosine 3-Monooxygenase; VEGFA gene; Woman; Xenograft procedure; aldehyde dehydrogenase 1; aldehyde dehydrogenases; angiogenesis; arginase; base; cancer cell; cancer stem cell; cell type; cytokine; experimental study; improved; in vivo; macrophage; malignant breast neoplasm; mortality; neoplastic cell; neuregulin-4; new therapeutic target; novel; psoriasin; receptor for advanced glycation endproducts; small hairpin RNA; stem cell biomarkers; trait; triple-negative invasive breast carcinoma; tumor; tumor behavior; tumor growth; tumor microenvironment; tumor progression

African American (AA) women continue to suffer from high mortality rates from an aggressive form of breast cancer for which there is no treatment. Better understanding of the unique properties of AA tumor cells and the microenvironment that supports its growth might improve clinical outcomes. Macrophages are a lynchpin in tumor microenvironment regulation. Although high macrophage infiltration and increased angiogenesis are unique characteristics of AA breast tumors, mechanisms that support these biological processes remain poorly understood. We have recently demonstrated, for the first time that increase in beige/brown adipose phenotype promote development of xenografts from breast cancer cells. We have subsequently demonstrated that expression of beige markers is significantly increased in both xenografts obtained from AA triple- negative (TN) breast cancer cells as well as in AA TN breast tumors. Based on our published and preliminary data, we hypothesize that “cross-talk between tumor cells and beige adipocytes generates a unique microenvironment that promotes M2 macrophage phenotype and is conducive to high angiogenesis.” We will test our hypothesis with the following Specific Aims: Aim 1: Determine whether i) M2 macrophages increase beige adipose phenotype in breast cancer cells and ii) beige adipose cells crosstalk with tumor cells to increase aggressive behavior in AA TN breast tumors. Aim 2: Determine the molecular mechanisms by which beige adipocytes in AA breast tumors support and sustain M2 macrophage population. Aim 3: Determine whether Th2 cytokines in AA TN breast tumor microenvironment promote proliferation and commitment of bi-potent adipose precursors (AP) to beige lineage. Effect of depletion of tissue resident macrophages and tyrosine hydroxylase (TH) expressed in these macrophages, on beige adipose phenotype as well as tumor growth in-vivo will be analyzed. Co-culture experiments with adipocytes enriched in beige phenotype and AA TN breast cancer cells will be performed to elucidate mechanisms that support M2 macrophages/angiogenesis. We will examine the possible role of psoriasin, and beige adipose-enriched secretory factors Neuregulin 4 (Nrg4) and Meteorin- like (Metrnl) during the cross-talk between cancer cells and beige adipocytes. We will further analyze the role of psoriasin in promoting MCSC (ALDH+)-induced xenograft growth. Depletion/enrichment of breast tumor cells with adipose precursor PDGFRα cells will be examined for tumor growth, beige adipose/M2 markers and tumor growth. Increased understanding of detailed molecular mechanisms by which beige adipocytes sustain critical threshold of M2 macrophage population in tumor microenvironment and contribute to tumor progression may provide outstanding opportunity for therapeutic intervention for these aggressive AA TN breast tumors.

非裔美国人（AA）妇女继续遭受高死亡率从一个积极的 乳腺癌是一种无法治疗的癌症。更好地了解独特的 AA肿瘤细胞的特性和支持其生长的微环境可能会改善 临床结果。肿瘤微环境调节的关键是大细胞。虽然 高巨噬细胞浸润和增加的血管生成是AA乳腺的独特特征 肿瘤，支持这些生物过程的机制仍然知之甚少。我们有 最近首次证明，米色/棕色脂肪表型的增加促进了 从乳腺癌细胞发展异种移植物。我们随后证明， 米色标记物的表达在从AA三联体获得的两种异种移植物中显著增加， 阴性（TN）乳腺癌细胞以及AA TN乳腺肿瘤中。根据我们发布的和 根据初步数据，我们假设“肿瘤细胞和米色脂肪细胞之间的相互作用 产生独特的微环境，促进M2巨噬细胞表型， 有助于高血管生成。”我们将通过以下具体目标来检验我们的假设： 目的1：确定i）M2巨噬细胞是否增加乳房中的米色脂肪表型 癌细胞和ii）米色脂肪细胞与肿瘤细胞相互作用以增加攻击行为 在AA TN乳腺肿瘤中。目的2：确定米色脂肪细胞 在AA乳腺肿瘤中支持和维持M2巨噬细胞群体。目标3：确定是否 AA TN乳腺肿瘤微环境中的Th 2细胞因子促进乳腺癌细胞的增殖和定向， 双能脂肪前体（AP）至米色谱系。组织驻留物消耗的影响 巨噬细胞和酪氨酸羟化酶（TH）在这些巨噬细胞表达，在米色脂肪 将分析表型以及体内肿瘤生长。共培养实验 将对富含米色表型的脂肪细胞和AA TN乳腺癌细胞进行检测， 阐明支持M2巨噬细胞/血管生成的机制。我们将研究可能的 银屑病的作用，米色脂肪富集分泌因子神经调节蛋白4（Nrg 4）和镍纹蛋白- 就像（Metrnl）在癌细胞和米色脂肪细胞之间的相互作用期间。我们将进一步 分析牛皮癣素在促进MCSC（ALDH+）诱导的异种移植物生长中的作用。 将检查乳腺肿瘤细胞与脂肪前体PDGFRα细胞的耗竭/富集 对于肿瘤生长，米色脂肪/M2标志物和肿瘤生长。更加了解 米色脂肪细胞维持M2临界阈值的详细分子机制 肿瘤微环境中的巨噬细胞群体并促进肿瘤进展可能 为这些侵袭性AA TN乳腺癌的治疗干预提供了绝佳的机会 肿瘤的

项目成果

DUSP9-mediated reduction of pERK1/2 supports cancer stem cell-like traits and promotes triple negative breast cancer.

• 发表时间: 2020-10
• 期刊: American journal of cancer research
• 影响因子: 5.3
• 作者: Thalia Jimenez;Albert Barrios;A. Tucker;Javier Collazo;Nataly Arias;S. Fazel;Melanie Baker;M. Halim;T. Huynh;R. Singh;S. Pervin

Nicotine Synergizes with High-Fat Diet to Induce an Anti-Inflammatory Microenvironment to Promote Breast Tumor Growth.

• DOI: 10.1155/2020/5239419
• 发表时间: 2020
• 期刊: Mediators of inflammation
• 影响因子: 4.6
• 作者: Jimenez T;Friedman T;Vadgama J;Singh V;Tucker A;Collazo J;Sinha S;Hikim AS;Singh R;Pervin S
• 通讯作者: Pervin S

Human Brown Adipose Tissue and Metabolic Health: Potential for Therapeutic Avenues.

• DOI: 10.3390/cells10113030
• 发表时间: 2021-11-05
• 期刊: Cells
• 影响因子: 6
• 作者: Singh R;Barrios A;Dirakvand G;Pervin S
• 通讯作者: Pervin S