Rewired Signaling at the Nexus of Melanoma Metastasis and Resistance
黑色素瘤转移和耐药性之间的信号重新连接
基本信息
- 批准号:9213360
- 负责人:
- 金额:$ 113.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-02-02 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:ATF2 geneAutophagocytosisBRAF geneBreast Cancer PatientCell DeathCellular Stress ResponseComplementDevelopmentDrug resistanceEpigenetic ProcessExhibitsFutureGap JunctionsGene ExpressionGeneticGlutamineHypoxiaHypoxia PathwayImmunologic SurveillanceInvestigationLesionMAPK8 geneMalignant neoplasm of pancreasMalignant neoplasm of prostateMetabolismMethodsModalityMonitorMutateMutationNeoplasm MetastasisNutrientOncogenicPDPK1 genePhenotypePhosphotransferasesPlayRNA SplicingResistanceRoleSignal TransductionStressStress Response SignalingTumor Suppressor Proteinsbasebiological adaptation to stresscancer cellendoplasmic reticulum stressgain of functioninhibitor/antagonistmelanomaneoplastic cellnovelnovel therapeuticspreventprogramspublic health relevanceresponsetherapy resistanttranscription factortumorubiquitin ligase
项目摘要
DESCRIPTION (provided by applicant): Malignant cells are continuously exposed to extrinsic (hypoxia, limited access to nutrients, immune surveillance) and intrinsic (oncogenic insults) stresses that culminate in activation of the hypoxia and endoplasmic reticulum stress (ERS) response programs. Tumor cell adaptation to these challenges depends on both genetic (acquisition of new mutations) and epigenetic (modulation of gene expression) mechanisms that underlie tumor survival, metastasis, and resistance to therapy; also known as plasticity. Over the past two decades, my lab has focused on understanding the cellular stress response, particularly the contribution of kinases and ubiquitin ligases. Our studies established a number of paradigms in stress adaptation, with demonstrated significance for the development, progression, and drug resistance of both melanoma and prostate cancer. We defined how subcellular localization dictates the oncogenic or tumor suppressor activity of ATF2, and showed that this is regulated by the AGC kinase PKC. Based on this discovery we performed a screen for inhibitors of this transcription factor-ostensibly undruggable targets- based on altered subcellular localization. Our other recent discovery of a spliced form of ATF2 that exhibits a gain-of-function phenotype will enable us to further redefine the function of ATF2 in melanoma. Further, we identified a mechanism of rewired signaling in which ERK impacts JNK with concomitant effects on PDK1, the master regulator of AGC kinases. This led us to demonstrate the key role played by PDK1 in melanoma. Our future studies will continue to investigate how PDK1 and its downstream targets contribute to melanoma metastasis and drug resistance. Our discovery that the ubiquitin ligases Siah1/2 control the hypoxia response revealed their roles in melanoma and the most aggressive forms of prostate cancer. Siah1/2 also control stress response signaling, establishing a mechanism for commitment to cell death under ischemic conditions. This established the basis upon which we will develop and evaluate first-in-class Siah inhibitors for prostate cancer and melanoma metastasis and resistance. We also recently determined that the RNF5 ubiquitin ligase regulates both autophagy and glutamine metabolism and established a new method to stratify breast cancer patients to select therapies. Lastly, the discovery that RNF125 ubiquitin ligase is a key regulator of melanoma resistance to BRAF inhibitors will drive an investigation in pancreatic cancer, a fraction of which carry mutated
RNF125. Collectively, our discoveries reveal that the tumor cell response to stress, which underlies their plasticity, involves the cooperation between rewired signaling and genetic lesions. Our proposed studies will establish novel mechanisms underlying tumor plasticity, enabling the development of novel agents for predicting, monitoring, and preventing tumor metastasis and resistance.
描述(由适用提供):恶性细胞不断暴露于外在(缺氧,有限的营养物质,免疫监视)和内在的(致癌性损伤)应力,这些压力最终导致激活的激活和内质性网状应激(ERS)反应程序。肿瘤细胞对这些挑战的适应取决于遗传(新突变的获取)和表观遗传学(基因表达的调节)机制,这些机制是肿瘤存活,转移和对治疗的耐药性的基础。也称为可塑性。在过去的二十年中,我的实验室专注于了解细胞应激反应,尤其是激酶和泛素连接酶的贡献。我们的研究在压力适应中建立了许多范式,对黑色素瘤和前列腺癌的发育,进展和耐药性具有重要意义。我们定义了亚细胞定位如何决定ATF2的致癌或肿瘤抑制活性,并表明这受AGC激酶PKC的调节。基于这一发现,我们对这种转录因子的抑制剂进行了屏幕,这是基于不良的亚细胞定位的不良目标。我们最近发现的ATF2的剪接形式的表现出功能型表型将使我们能够进一步重新定义ATF2在黑色素瘤中的功能。此外,我们确定了一种重新接线信号传导的机制,在该机制中,ERK对JNK产生了对AGC激酶的主要调节剂PDK1的影响。这使我们展示了PDK1在黑色素瘤中扮演的关键角色。我们未来的研究将继续研究PDK1及其下游靶标如何促进黑色素瘤转移和耐药性。我们发现,泛素连接酶SIAH1/2控制缺氧反应表明它们在黑色素瘤和前列腺癌最具侵略性的形式中的作用。 SIAH1/2还控制应力响应信号,建立了在缺血性条件下承诺细胞死亡的机制。这确立了我们将开发和评估前列腺癌和黑色素瘤转移和耐药的第一类SIAH抑制剂的基础。我们最近还确定,RNF5泛素连接酶调节自噬和谷氨酰胺代谢,并建立了一种对乳腺癌患者进行选择以选择疗法的新方法。最后,发现RNF125泛素连接酶是对BRAF抑制剂抗黑色素瘤的关键调节剂的发现将推动胰腺癌的研究,其中一小部分携带突变
RNF125。总体而言,我们的发现表明,肿瘤细胞对应激的反应(其可塑性是基础)涉及重新信号传导和遗传病变之间的合作。我们提出的研究将建立肿瘤可塑性的基本机制,从而使新型药物的发展用于预测,监测和预防肿瘤转移和抗性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
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Ze'ev A Ronai其他文献
Ze'ev A Ronai的其他文献
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{{ truncateString('Ze'ev A Ronai', 18)}}的其他基金
Control of Protein Synthesis by the UPS Under Stress
应激状态下 UPS 对蛋白质合成的控制
- 批准号:
9177401 - 财政年份:2016
- 资助金额:
$ 113.75万 - 项目类别:
Control of Protein Synthesis by the UPS Under Stress
应激状态下 UPS 对蛋白质合成的控制
- 批准号:
9301496 - 财政年份:2016
- 资助金额:
$ 113.75万 - 项目类别:
Rewired Signaling at the Nexus of Melanoma Metastasis and Resistance
黑色素瘤转移和耐药性之间的信号重新连接
- 批准号:
10080714 - 财政年份:2016
- 资助金额:
$ 113.75万 - 项目类别:
Rewired Signaling at the Nexus of Melanoma Metastasis and Resistance
黑色素瘤转移和耐药性之间的信号重新连接
- 批准号:
8955610 - 财政年份:2016
- 资助金额:
$ 113.75万 - 项目类别:
Control of Protein Synthesis by the UPS Under Stress
应激状态下 UPS 对蛋白质合成的控制
- 批准号:
9512865 - 财政年份:2016
- 资助金额:
$ 113.75万 - 项目类别:
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