ADAM12 in Breast Tumor Initiating Cells

乳腺肿瘤起始细胞中的 ADAM12

• 批准号: 8792604
• 负责人: Anna Zolkiewska
• 金额: $ 31.13万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792604
• 关键词: Accounting; Adverse effects; Biology; Breast Cancer Cell; Breast Epithelial Cells; Cell Surface Proteins; Cell surface; Cells; Cleaved cell; Clinical Data; Data; Detection; Diagnostics Research; Disintegrins; Down-Regulation; Epidermal Growth Factor; Estrogen receptor negative; Family; Goals; Health; Heterogeneity; In Vitro; Knowledge; Laboratories; Left; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Messenger RNA; Meta-Analysis; Metalloproteases; Methods; MicroRNAs; Molecular; Neoadjuvant Therapy; Neoplasm Metastasis; Normal tissue morphology; Outcome; Outcome Study; Pathway interactions; Patients; Pattern; Population; RNA Splicing; Radiation therapy; Reagent; Recurrence; Research; Residual Tumors; Resistance; Rest; Role; Signal Pathway; Signal Transduction; Surface; Testing; Time; Transforming Growth Factors; Translational Research; Up-Regulation; Variant; Work; autocrine; base; cancer cell; cancer therapy; chemotherapy; epithelial to mesenchymal transition; improved; in vivo; innovation; malignant breast neoplasm; member; new therapeutic target; notch protein; novel marker; outcome forecast; paracrine; self-renewal; stem; therapeutic target; tool; transcription factor; tumor; tumorigenic

DESCRIPTION (provided by applicant): Breast tumor initiating cells (BTICs), also referred to as cancer stem-like cells, drive breast tumor formation, recurrence, and metastasis. BTICs are largely resistant to chemotherapy and radiotherapy, posing a major obstacle to effective cancer treatment. Therefore, there is an urgent need to develop approaches that would not only destroy the existing BTICs, but would also detect and block the emergence of new BTICs. The long-term goal of our research is to understand how BTICs differ from the rest of breast tumor cells and how this knowledge can be used to develop new anti-BTICs strategies. The objective of this application is to evaluate ADAM12, a member of the ADAM family of cell-surface disintegrin-metalloproteases, as a novel marker and a novel therapeutic target in BTICs. Our central hypothesis is that ADAM12 is specifically induced in BTICs and, by modulating autocrine/paracrine cell signaling, it increases the formation, self-renewal, and/or tumorigenic potential of BTICs. To test our hypothesis, we will pursue the following Specific Aims: 1. Identify mechanisms responsible for the selective up-regulation ADAM12 expression in BTIC-enriched populations of cells. 2. Evaluate ADAM12 as a selective marker for BTICs. 3. Determine the role of ADAM12 in the biology of BTICs. Our studies are significant because they strive to produce new research and diagnostic tools for detection of BTICs and to develop new therapies to target BTICs, which are of critical importance to improve patient survival. The proposed research is innovative because for the first time it takes into account the molecular heterogeneity of breast tumors and new information on the expression pattern of ADAM12 in various molecular subtypes of breast cancer.

描述（由申请人提供）：乳腺肿瘤起始细胞（BTIC），也称为癌症干细胞样细胞，驱动乳腺肿瘤形成、复发和转移。 BTIC 在很大程度上对化疗和放疗具有抵抗力，这对有效的癌症治疗构成了主要障碍。因此，迫切需要开发不仅能摧毁现有 BTIC，还能检测和阻止新 BTIC 出现的方法。我们研究的长期目标是了解 BTIC 与其他乳腺肿瘤细胞有何不同，以及如何利用这些知识来开发新的抗 BTIC 策略。本申请的目的是评估 ADAM12（细胞表面解整合素金属蛋白酶 ADAM 家族的成员）作为 BTIC 中的新型标记物和新型治疗靶点的作用。我们的中心假设是 ADAM12 在 BTIC 中被特异性诱导，并且通过调节自分泌/旁分泌细胞信号传导，它增加了 BTIC 的形成、自我更新和/或致瘤潜力。为了检验我们的假设，我们将追求以下具体目标： 1. 确定 负责在富含 BTIC 的细胞群中选择性上调 ADAM12 表达的机制。 2. 评估 ADAM12 作为 BTIC 的选择标记。 3. 确定 ADAM12 在 BTIC 生物学中的作用。我们的研究意义重大，因为他们致力于开发用于检测 BTIC 的新研究和诊断工具，并开发针对 BTIC 的新疗法，这对于提高患者生存率至关重要。该研究具有创新性，因为它首次考虑到乳腺肿瘤的分子异质性以及ADAM12在乳腺癌各种分子亚型中表达模式的新信息。