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

描述(由申请人提供)：侵袭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所驱动的肿瘤转移多步骤过程中的关键事件。我们现在发现，非受体酪氨酸激酶Ab1家族Ab1(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，在调节癌细胞侵袭中发挥关键作用。我们发现，Abl激酶是上皮性癌细胞侵袭和基质降解所必需的，并发现了一条新的信号通路，将Abl激酶与乳腺癌细胞中基质金属蛋白酶MT1-MMPs的调控联系在一起。此外，我们还发现，在Her2和激素受体阴性的一组乳腺癌细胞株中，内源性Abl激酶被过度激活。此外，激活的Abl激酶的表达引起与癌症进展相关的上皮细胞极性的显著破坏。基于这些发现，我们假设通过调节侵袭性程序，Abl激酶是上皮性肿瘤转移所必需的，因此以抑制Abl激酶为靶点的联合疗法可能被用于治疗侵袭性乳腺肿瘤的子集。为此，我们提出了以下目标：1)确定人乳腺癌细胞中激活的Abl激酶的磷酸化蛋白质组特征。了解激活的Abl激酶在乳腺肿瘤中诱导的分子特征将有助于识别可能受益于经批准的和新型的Abl激酶抑制剂靶向治疗的患者；2)阐明Abl激酶调节乳腺癌细胞侵袭的机制；3)通过小鼠模型确定Abl激酶在乳腺肿瘤进展和转移中的作用。这些目标将共同揭示依赖Abl的信号网络，该网络调节驱动癌症肿瘤进展和转移的侵袭性程序。这些研究的长期目标是开发新的治疗方法，比目前治疗特定肿瘤亚型的方法具有更高的特异性和更低的毒性。抑制Abl激酶有望同时阻断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的激酶的激活上。

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.