A role for c-Abl/Arg in melanoma progression

c-Abl/Arg 在黑色素瘤进展中的作用

• 批准号: 9126253
• 负责人: RINA PLATTNER
• 金额: $ 30.86万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-12 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9126253
• 关键词: ABL1 gene; Anoikis; Biochemical; Biological; Cathepsin L; Cathepsins; Cell Adhesion; Cell Communication; Cell Line; Cell Survival; Cell-Cell Adhesion; Cells; Clinic; Clinical; Clinical Research; Clinical Trials; Coculture Techniques; Data; Dermal; Detection; Development; Disease; Disease remission; Drug Combinations; Drug Targeting; Endothelial Cells; Environment; Experimental Designs; Extravasation; FDA approved; Fibroblasts; Genetic Transcription; Genetically Engineered Mouse; Goals; Imatinib; In Vitro; Lead; Lung; MEKs; Matrix Metalloproteinases; Mean Survival Times; Mediating; Melanoma Cell; Metastatic Melanoma; Molecular; Mouse Strains; Mutation; N-Cadherin; NME1 gene; Neoplasm Metastasis; Outcome; Pathway interactions; Patients; Peptide Hydrolases; Phosphotransferases; Play; Positioning Attribute; Prevention; Protein Tyrosine Kinase; RNA Interference; Ras/Raf; Regimen; Research; Residual state; Resistance; Role; STAT3 gene; STI571; Scientist; Seminal; Signal Pathway; Signal Transduction; Solid Neoplasm; Staging; Survival Rate; Testing; Transcriptional Activation; Treatment Protocols; UV-induced melanoma; Universities; Xenograft Model; base; c-abl Proto-Oncogenes; chemotherapeutic agent; design; efficacy testing; gain of function; inhibitor/antagonist; innovation; insight; killings; leukemia; loss of function; matrigel; melanoma; migration; mutant; novel; novel drug combination; novel therapeutics; prevent; research study; three dimensional cell culture; tool

DESCRIPTION (provided by applicant): Despite 35 years of clinical trials, there has been little improvement in five-year survival rates with any chemotherapeutic regimen for the treatment of metastatic melanoma. Here, we demonstrate a previously unrecognized role for Abl kinases in melanoma cells. We found that c-Abl/Arg non-receptor tyrosine kinases are activated in primary melanomas and in melanoma cell lines, and promote proliferation, survival, cell-cell adhesion, migration, invasion, and lung colonization/metastasis. In addition, c-Abl/Arg promote matrigel invasion via STAT3 and MMP-dependent pathways; increase cell-cell adhesion; and dramatically induce degradation of a metastasis suppressor. Moreover, drugs targeting c-Abl/Arg and Raf/MEK/ERK pathways cooperate to decrease melanoma viability. Based on these novel findings, we hypothesize that c-Abl/Arg activate novel pathways that cooperate with B-Raf to promote melanoma cell-cell adhesion, migration, invasion, and metastasis. We propose a comprehensive hypothesis-driven experimental design that will establish Abl kinases as novel and exploitable drug targets for metastatic melanoma. Aim 1 will define molecular pathways by which Abl kinases promote cell-cell adhesion, migration, and invasion. To achieve our objective, we will combine biochemical, molecular, and cell biological approaches using RNAi, pharmacological inhibitors, constitutively active forms of c-Abl/Arg, rescue experiments, 2D/3D cell culture, and melanoma- endothelial co-cultures to identify migration, invasion, and cell-cell adhesion signaling pathways driven by c- Abl/Arg. Aim 2 will test the prediction that c-Abl/Arg cooperates with Abl-independent pathways (e.g. B-Raf) to promote melanoma cell-cell, adhesion, migration, and invasion. Finally, three complementary approaches will be utilized in Aim 3 to identify mechanisms by which c-Abl/Arg promote metastasis. A novel GEM model that develops metastatic UV-induced melanomas, and lung colonization and spontaneous metastasis xenograft models will be used to test the prediction that blocking c-Abl/Arg-dependent signaling pathways inhibits metastatic progression. We also will test whether B-Raf and c-Abl/Arg inhibitors cooperate to prevent metastasis of melanomas harboring B-Raf mutations. The data obtained from this proposal not only will allow us to gain insight into the fundamental mechanisms by which c-Abl/Arg drive invasion and metastasis, but also will lead to clinical studies testing the efficacy of c-Abl/Arg inhibitors for treating metastatic disease.

描述（由申请人提供）：尽管有35年的临床试验，但用于治疗转移性黑色素瘤的任何化疗方案的五年生存率几乎没有改善。在这里，我们证明了一个以前未被认识的作用Abl激酶在黑色素瘤细胞。我们发现c-Abl/Arg非受体酪氨酸激酶在原发性黑色素瘤和黑色素瘤细胞系中被激活，并促进增殖、存活、细胞-细胞粘附、迁移、侵袭和肺定殖/转移。此外，c-Abl/Arg通过STAT 3和MMP依赖性途径促进基质胶侵袭;增加细胞-细胞粘附;并显著诱导转移抑制因子的降解。此外，靶向c-Abl/Arg和Raf/MEK/ERK途径的药物协同降低黑色素瘤活力。基于这些新的发现，我们假设c-Abl/Arg激活新的途径，与B-Raf合作，促进黑色素瘤细胞-细胞粘附，迁移，侵袭和转移。我们提出了一个全面的假设驱动的实验设计，将建立Abl激酶作为转移性黑色素瘤的新的和可利用的药物靶点。目标1将定义Abl激酶促进细胞间粘附、迁移和侵袭的分子途径。为了实现我们的目标，我们将使用RNAi、药理学抑制剂、c-Abl/Arg的组成型活性形式、拯救实验、2D/3D细胞培养和黑色素瘤-内皮细胞共培养来结合联合收割机生物化学、分子和细胞生物学方法，以鉴定由c-Abl/Arg驱动的迁移、侵袭和细胞-细胞粘附信号通路。目的2将测试c-Abl/Arg与非依赖于B-Raf的通路（例如B-Raf）合作以促进黑素瘤细胞-细胞、粘附、迁移和侵袭的预测。最后，三个互补的方法将用于目标3，以确定c-Abl/Arg促进转移的机制。一种新的GEM模型，发展转移性UV诱导的黑色素瘤，肺定植和自发转移异种移植模型将用于测试预测，阻断c-Abl/Arg依赖性信号传导途径抑制转移进展。我们还将测试B-Raf和c-Abl/Arg抑制剂是否合作以防止携带B-Raf突变的黑色素瘤的转移。从该提案中获得的数据不仅使我们能够深入了解c-Abl/Arg驱动侵袭和转移的基本机制，而且还将导致临床研究测试c-Abl/Arg抑制剂治疗转移性疾病的功效。