The SMYD3-ERK5 signaling module in pancreatic cancer

 我的长期职业目标是领导一个富有成效的学术研究小组，通过开展有影响力的癌症生物学研究来促进科学发展，并指导下一代敬业的科学家。我特别感兴趣的是RAS驱动的肿瘤的癌症发展和抵抗治疗的机制。胰腺导管腺癌(PDAC)是最致命的癌症之一，几乎所有的肿瘤都是由致癌RAS的激活引起的。不幸的是，在过去的几十年里，PDAC的死亡率几乎与发病率持平。我的主要目标是在PDAC细胞中寻找新的治疗靶点，以指导PDAC患者开发新的有效药物和治疗方法。K99/R00方案的一个主要目的是阐明与PDAC有关的一个新的信号模块：在这个模块中，SMYD3赖氨酸甲基转移酶激活MAP3K2激酶，进而激活MEK5激酶，导致下游ERK5激酶的激活。第二个重要目标是揭示针对RAS途径的药物耐药的分子机制。首先，我将重点确定ERK5在PDAC的启动和进展中的作用。MEK5-ERK5通路与细胞存活和细胞运动有关，但其在PDAC中的作用从未被研究过。目标 1将测试一个假设，即我最近在PDAC中观察到的SMYD3-ERK5信号模块的激活，通过促进胰腺细胞的可塑性、增殖和在致癌RAS反应中损害细胞凋亡来促进早期癌症进展。我将使用Genetic 以及在PDAC小鼠模型、患者来源的肿瘤异种移植和癌细胞系中测试这一假说的药理学方法。在典型的RAS途径中使用激酶抑制剂的临床试验结果令人失望，部分原因是耐药肿瘤的迅速出现。我已经建立了临床前模型来研究肿瘤对RAS途径抑制剂的耐药性，并发现在肿瘤复发期间SMYD3-ERK5活性放大。目的2将利用遗传学和药理学方法研究SMYD3-ERK5信号模块在体内和体外耐药肿瘤中的功能作用。最后，在目标3中，我将对ERK5的转录靶点和相互作用的蛋白质伙伴进行无偏见的筛选，以阐明其在PDAC细胞中的作用机制，并确定PDAC发展和对RAS途径抑制剂的耐药性的新的关键调节因子。候选靶点，包括初步确定的YAP1转录因子，将在我为快速研究体内疾病发展的假定调控因素而开发的一种新的人类PDAC小鼠模型中进行测试。K99/R00培训奖将使我能够实施这一变革性的项目，进一步发展我目前在小鼠遗传学和癌症生物学方面的技能，同时还让我获得胰腺癌临床方面的知识，以及生化信号和系统生物学方面的新专业知识。

 DESCRIPTION (provided by applicant): My long-term career goal is to lead a productive academic research group, promoting science by conducting impactful cancer biology research and mentoring the next generation of dedicated scientists. I am particularly interested in the mechanisms of cancer development and resistance to therapy in Ras-driven tumors. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, and it is almost universally driven by activation of oncogenic Ras. Unfortunately, PDAC mortality rates have remained almost equal to incidence rates over the past few decades. My main objective is to identify novel therapeutic targets in PDAC cells to guide the development of new efficacious drugs and treatment approaches in PDAC patients. A major goal of this K99/R00 proposal is to elucidate a novel signaling module implicated in PDAC: in this module, the SMYD3 lysine methyltransferase activates the MAP3K2 kinase, which in turn activates the MEK5 kinase, leading to activation of the downstream ERK5 kinase. A second important goal is to uncover molecular mechanisms promoting resistance to drugs targeting the Ras pathway. First, I will focus on defining the role of ERK5 in the initiation and progression of PDAC. The MEK5-ERK5 pathway has been implicated in cell survival and cell motility but its role in PDAC has never been investigated. Aim 1 will test the hypothesis that activation of the SMYD3-ERK5 signaling module, which I have recently observed in PDAC, facilitates early cancer progression by promoting pancreatic cell plasticity, proliferation, and impairing apoptosis in response to oncogenic Ras. I will use genetic and pharmacological approaches to test this hypothesis in mouse models of PDAC, patient derived tumor xenografts, and cancer cell lines. Clinical trials with inhibitors of kinases in the canonical Ras pathway have had disappointing results, in part because of the rapid emergence of resistant tumors. I have generated pre-clinical models to study tumors resistant to Ras pathway inhibitors and found amplification of SMYD3-ERK5 activity during tumor relapse. Aim 2 will utilize genetic and pharmacological approaches to characterize the functional role of the SMYD3- ERK5 signaling module in resistant tumors in vivo and in vitro. Finally, in Aim 3, I will perform an unbiased screen of transcriptional targets and interacting protein partners of ERK5 to elucidate its mechanisms of action in PDAC cells and identify novel key regulators of PDAC development and resistance to Ras pathway inhibitors. Candidate targets, including preliminarily identified YAP1 transcription factor, will be tested in a novel mouse model of human PDAC that I have developed for rapid investigation of putative regulators of disease development in vivo. A K99/R00 training award will allow me to carry out this transformative project, further developing my current skills in mouse genetics and cancer biology, while also allowing me to acquire knowledge in clinical aspects of pancreatic cancer and new expertise in biochemical signaling and systems biology.