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

基本信息

批准号：
8199099
负责人：
Ann Marie Pendergast
金额：
$ 31.21万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8199099
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

项目摘要

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. PUBLIC HEALTH RELEVANCE: Disruption of cell polarity and activation of an invasive program are critical events in the multi-step process of tumor metastasis. We have identified the Abl family of nonreceptor tyrosine kinases as critical regulators of cell polarity and cancer cell invasion. We found that Abl kinases, which are activated downstream of multiple RTKs, are also activated downstream of chemokine receptors in breast cancer cells and are required for cancer cell invasion and matrix degradation. Results from the proposed studies have wide-ranging implications for the development of novel therapeutic approaches with greater specificity and reduced toxicity than current therapies for the treatment of invasive solid tumors. Inhibition of the Abl kinases will result in the simultaneous block of multiple signaling pathways required for the invasion of epithelial tumors driven by the activation of RTKs and/or chemokines 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的激活驱动的肿瘤转移的多步骤过程中的关键事件。我们现在表明，非受体酪氨酸激酶 Abl 家族 Abl (Abl1) 和 Arg (Abl2) 在多受体酪氨酸激酶 (RTK) 下游被激活，也被趋化因子受体激活，并在调节癌细胞侵袭。我们证明 Abl 激酶是上皮癌细胞侵袭和基质降解所必需的，并确定了一种新的信号通路，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 Her2 和激素受体阴性的乳腺癌细胞系子集中过度激活。此外，激活的 Abl 激酶的表达会引起上皮细胞极性的显着破坏，这与癌症进展相关。基于这些发现，我们假设 Abl 激酶是通过调节侵袭性程序来实现上皮肿瘤子集的转移所必需的，因此可以利用以抑制 Abl 激酶为目标的联合疗法来治疗侵袭性乳腺肿瘤的子集。为此，我们提出以下目标：1) 鉴定人乳腺癌细胞中激活的 Abl 激酶的磷酸化蛋白质组学特征。了解乳腺肿瘤中激活的 Abl 激酶诱导的分子特征将有助于识别可能受益于已批准的新型 Abl 激酶抑制剂的靶向治疗的患者； 2）阐明Abl激酶调节乳腺癌细胞侵袭的机制； 3) 使用小鼠模型确定 Abl 激酶在乳腺肿瘤进展和转移中的作用。这些目标共同将揭示 Abl 依赖性信号网络，该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开发新的治疗方法，与目前治疗特定肿瘤亚型的疗法相比，具有更高的特异性和更低的毒性。 Abl 激酶的抑制预计会同时阻断肿瘤侵袭所需的多种信号传导途径，这些信号传导途径集中在这些独特激酶的激活上。公共卫生相关性：细胞极性的破坏和侵入性程序的激活是肿瘤转移多步骤过程中的关键事件。我们已经确定非受体酪氨酸激酶 Abl 家族是细胞极性和癌细胞侵袭的关键调节因子。我们发现，在多个 RTK 下游被激活的 Abl 激酶也在乳腺癌细胞中的趋化因子受体下游被激活，并且是癌细胞侵袭和基质降解所必需的。拟议研究的结果对于开发新的治疗方法具有广泛的影响，这些方法比目前治疗侵袭性实体瘤的疗法具有更高的特异性和更低的毒性。 Abl 激酶的抑制将导致同时阻断由 RTK 和/或趋化因子激活驱动的上皮肿瘤侵袭所需的多个信号通路，这些信号通路集中在这些独特激酶的激活上。