ADAM12 in Breast Tumor Initiating Cells

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抗性，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，而且能发现和阻止新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的不同之处，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细胞表面去整合素-金属蛋白酶的ADAM家族成员ADAM 12作为BTIC中的新型标记物和新型治疗靶点。我们的中心假设是，ADAM 12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BTIC的形成、自我更新和/或致瘤潜力。为了验证我们的假设，我们将追求以下具体目标：1。识别 在BTIC富集的细胞群中选择性上调ADAM 12表达的机制。2.评估ADAM 12作为BTIC的选择性标志物。3.确定ADAM 12在BTIC生物学中的作用。我们的研究意义重大，因为它们致力于为BTIC的检测提供新的研究和诊断工具，并开发针对BTIC的新疗法，这对提高患者生存率至关重要。这项研究具有创新性，因为它首次考虑到了乳腺肿瘤的分子异质性，以及有关ADAM 12在乳腺癌各种分子亚型中表达模式的新信息。

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.