Kinase Target of Diverse Cell Surface Receptors in Cancer Invasion and Metastasis

癌症侵袭和转移中多种细胞表面受体的激酶靶点

• 批准号: 8458615
• 负责人: Ann Marie Pendergast
• 金额: $ 30.22万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-21 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458615
• 关键词: 3-Dimensional; Actins; Affect; Automobile Driving; Blood Circulation; Breast Cancer Cell; Cancer Patient; Cancer cell line; Cell Polarity; Cell Surface Receptors; Cell Survival; Cell-Matrix Junction; Cells; Cellular Morphology; Chemotaxis; Chimeric Proteins; Chromosomal translocation; Colorectal Neoplasms; Combined Modality Therapy; Cytoskeleton; Data; Development; Distant; Embryo; Employee Strikes; Epithelial; Epithelial Cells; Event; Extracellular Matrix; Extravasation; Family; Genes; Goals; Growth; Growth Factor; Hormone Receptor; Human; Knowledge; Ligands; Link; MMP14 gene; Malignant Neoplasms; Mammary Neoplasms; Matrix Metalloproteinases; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Oncogenic; Organ; Pathway interactions; Patients; Phosphotransferases; Physiological; Play; Process; Production; Protein Tyrosine Kinase; Publishing; Receptor Protein-Tyrosine Kinases; Regulation; Role; Signal Pathway; Signal Transduction; Site; Solid Neoplasm; Somatic Mutation; Specificity; Time; Toxic effect; Tumor Cell Invasion; Tumor Subtype; Tumor-Associated Process; Up-Regulation; Work; base; cancer cell; cell motility; chemokine; chemokine receptor; inhibitor/antagonist; kinase inhibitor; leukemia; malignant breast neoplasm; metastatic process; mortality; mouse development; mouse model; neoplastic cell; novel; novel therapeutic intervention; pancreatic neoplasm; programs; response; tumor; tumor progression

DESCRIPTION (provided by applicant): Activation of an invasive program is a critical event in the multi-step process of tumor metastasis driven by the activation of tyrosine kinases and ligand-stimulated chemokine receptors. We now show that the Abl family of nonreceptor tyrosine kinases, Abl (Abl1) and Arg (Abl2), which are activated downstream of multiple receptor tyrosine kinases (RTKs), are also activated by chemokine receptors and play a critical role in the regulation of cancer cell invasion. We show that Abl kinases are required for epithelial cancer cell invasion and matrix degradation and identify a novel signaling pathway that links the Abl kinases to the regulation of the matrix metalloproteinase MT1-MMP in breast cancer cells. Moreover, we found that endogenous Abl kinases are hyperactivated in a subset of breast cancer cell lines that are negative for Her2 and hormone receptors. Further, expression of activated Abl kinases elicits a striking disruption of epithelial cell polarity which is associated with cancer progression. Based on these findings, we hypothesize that Abl kinases are required for metastasis of a subset of epithelial tumors through regulation of invasive programs and thus combination therapies that target inhibition of Abl kinases might be exploited for the treatment of a subset of invasive breast tumors. To this end we propose the following aims: 1) Identify the phosphoproteomic signature for activated Abl kinases in human breast cancer cells. Knowledge of the molecular signature induced by activated Abl kinases in breast tumors will allow for identification of patients that might benefit from targeted therapy with approved and novel Abl kinase inhibitors; 2) Elucidate the mechanisms employed by Abl kinases to regulate breast cancer cell invasion; and 3) Define the role of Abl kinases in mammary tumor progression and metastasis using mouse models. Together these aims will uncover Abl-dependent signaling networks that regulate invasive programs that drive cancer tumor progression and metastasis. The long-term goal of these studies is to develop novel therapeutic approaches with greater specificity and reduced toxicity than those provided by current therapies for the treatment of specific tumor subtypes. Inhibition of the Abl kinases is expected to simultaneously block multiple signaling pathways required for tumor invasion that converge on the activation of these unique kinases.

描述（由申请人提供）：侵入性程序的激活是由酪氨酸激酶和配体刺激的趋化因子受体激活驱动的多步转移过程中的关键事件。现在，我们表明，非受体酪氨酸激酶，ABL（ABL1）和ARG（ABL2）的ABL家族，这些家族被多种受体酪氨酸激酶（RTK）激活，也被趋化因子受体激活，并在调节癌细胞侵袭的调节中起关键作用。我们表明，ABL激酶需要上皮性癌细胞浸润和基质降解，并确定一种新型的信号传导途径，将ABL激酶与乳腺癌细胞中基质金属蛋白酶MT1-MMP的调节联系起来。此外，我们发现内源性ABL激酶在乳腺癌细胞系的一部分中被过度激活，而HER2和激素受体为阴性。此外，激活的ABL激酶的表达引起了与癌症进展相关的上皮细胞极性的惊人破坏。根据这些发现，我们假设通过调节侵袭性程序的一部分上皮肿瘤的转移需要ABL激酶，因此可能利用靶向抑制ABL激酶的组合疗法来治疗侵袭性乳腺肿瘤的子集。为此，我们提出以下目的：1）确定人类乳腺癌细胞中激活的ABL激酶的磷酸蛋白质组学特征。了解乳腺肿瘤中激活的ABL激酶引起的分子特征的知识将允许鉴定可能受益于具有批准和新型ABL激酶抑制剂的靶向疗法的患者； 2）阐明ABL激酶用于调节乳腺癌细胞侵袭的机制； 3）使用小鼠模型来定义ABL激酶在乳腺肿瘤进展和转移中的作用。这些目标将共同发现依赖ABL的信号网络，这些信号网络调节驱动癌症肿瘤进展和转移的侵入性程序。这些研究的长期目标是，与当前治疗特定肿瘤亚型治疗的治疗方法相比，具有更特异性和毒性的新型治疗方法。预计抑制ABL激酶将同时阻止肿瘤入侵所需的多个信号通路，从而收敛着这些独特的激酶的激活。