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)妇女继续遭受侵略性的高死亡率之苦 一种没有治疗方法的乳腺癌。更好地理解独特的 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。巨噬细胞是肿瘤微环境调控的关键细胞。虽然 巨噬细胞高度浸润和血管生成增加是AA乳腺的独特特征 肿瘤，支持这些生物学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 乳腺癌细胞异种移植的研究进展。我们随后证明了 在AA三倍体移植获得的两种异种移植物中，米色标记的表达显著增加 阴性(TN)乳腺癌细胞以及AA TN乳腺肿瘤。基于我们发布的和 初步数据显示，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，并 有利于高血管生成。我们将通过以下具体目标来验证我们的假设： 目的1：确定I)M2巨噬细胞是否增加乳房米色脂肪表型 癌细胞和ii)米色脂肪细胞与肿瘤细胞串扰以增加侵袭行为 在AA-TN乳腺肿瘤中。目的2：确定米色脂肪细胞的分子机制 在AA中，乳腺肿瘤支持和维持M2巨噬细胞群。目标3：确定是否 AA、TN乳腺肿瘤微环境中Th2细胞因子促进细胞增殖和表达 双效脂肪前体(AP)到米色血统。组织残留物耗竭的影响 巨噬细胞和巨噬细胞表达的酪氨酸羟化酶(TH) 将分析表型以及体内肿瘤的生长情况。共培养实验与 富含米色表型的脂肪细胞和AA-TN乳腺癌细胞将被用于 阐明支持M2巨噬细胞/血管生成的机制。我们将研究可能的 银屑病和米色脂肪富集型分泌因子神经调节蛋白4(NRG4)和陨石素的作用 像(Metrnl)一样，在癌细胞和米色脂肪细胞之间的串扰中。我们将进一步 分析银屑病蛋白在促MCSC(ALDH+)诱导的异种移植瘤生长中的作用。 将检测脂肪前体PDGFRα细胞对乳腺肿瘤细胞的耗竭/浓缩 对于肿瘤生长，米色脂肪/M2标志物和肿瘤生长。加深了对 米色脂肪细胞维持M2临界阈值的详细分子机制 巨噬细胞在肿瘤微环境中的分布及其对肿瘤进展的影响 为这些侵袭性AA-TN乳房提供绝佳的治疗干预机会 肿瘤。

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

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

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