Mechanisms of translational output control in pancreatic cancer

胰腺癌翻译输出控制机制

• 批准号: 10356835
• 负责人: Simone Christine Hausmann
• 金额: $ 11.18万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356835
• 关键词: Ablation; Address; Attenuated; Award; Biochemical; Biological; Biology; Cancer Biology; Cancer Model; Cancer cell line; Cell Death; Cell Proliferation; Cells; Clinical; Consumption; Cytoplasmic Protein; Data; Data Set; Development; Disease; Foundations; Gene Expression Regulation; Genes; Genetic Translation; Goals; Growth; Human; Immune response; In Vitro; KRAS oncogenesis; KRAS2 gene; Knowledge; Lead; Learning; Link; Lysine; MAP2K1 gene; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mammalian Cell; Mentors; Messenger RNA; Meta-Analysis; Methylation; Methyltransferase; Mitogen-Activated Protein Kinases; Modeling; Modification; Molecular; Molecular Genetics; Mutate; Normal Cell; Oncogenic; Output; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathologic; Pathway interactions; Patients; Peptide Elongation Factor 1; Pharmacology; Phenotype; Physiological; Play; Pre-Clinical Model; Process; Production; Protein Biosynthesis; Protein Methyltransferases; Proteins; Proteomics; Regulation; Reporting; Research; Resistance; Resistance development; Role; Science; Scientist; Seminal; Signal Pathway; Signal Transduction; Site; Stress; Systems Biology; Techniques; Testing; Therapeutic; Training; Translations; Work; addiction; anticancer research; cancer cell; cancer initiation; career; clinically significant; effective therapy; experimental study; field study; human tissue; in vitro activity; in vivo; inhibitor; innovation; insight; interest; mRNA Expression; mouse genetics; mouse model; multidisciplinary; mutant; next generation; novel; novel therapeutics; pancreatic cancer cells; pancreatic cancer model; pancreatic ductal adenocarcinoma model; pancreatic tumorigenesis; patient derived xenograft model; response; ribosome profiling; skills; synergism; targeted treatment; therapeutic target; therapy resistant; tool development; translational approach; treatment response; tumor; tumor growth; tumor progression; tumorigenesis; tumorigenic

PROJECT SUMMARY 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 pancreatic ductal adenocarcinoma (PDAC). PDAC is one of the deadliest disease for which survival has not improved substantially over the past 25 years. There is currently no effective treatment for PDAC patients. The NCI, in accordance to the Recalcitrant Cancer Research Act, established a scientific framework in which the top priorities are the development of targeted therapeutics and therapies to overcome resistance to currently available agents. Our proposed research plan addresses these priorities by identifying poorly recognized non- histone lysine methyltransferase METTL10 as a critical regulator of eEF1A (eukaryotic elongation factor 1 alpha) a fundamental, non-ribosomal component of the mRNA translational machinery. Dysregulation of protein production is a hallmark of cancer and is linked to aberrant cell proliferation, survival, and alterations in both immune responses and cancer energetics. An overarching goal of this K99/R00 proposal focuses on the idea that lysine methylation of eEF1A regulates the rate of protein synthesis, the most energy-consuming process in the cell, and plays a critical role in human cancer growth. The goal of Aim 1 is to elucidate the role of METTL10 in pancreatic cancer driven by oncogenic KRAS. We will test the hypothesis that METTL10, via its methylation activity, cooperates with KRAS signaling to promote the unlimited expansion of cancer cells in vivo using mouse models of pancreas, in which KRAS pathway is frequently activated. We will also investigate the tumorigenic role of METTL10 in human tissue using patient-derived xenograft (PDX) models. Next, we will investigate the role of methylation on specific protein production using ribosome profiling techniques in mouse models of PDAC. Finally, we will explore potential synergies of METTL10 ablation in combination with inhibitors of MAP-kinases in pre-clinical models of pancreatic cancers. In Aim 2 we will characterize the physiologic catalytic activity of the METTL10 and its molecular functions in the regulation of eEF1A activity in vitro and mRNA translation biology in cells. We will also investigate the METTL10 and methylated eEF1A interacting partners and how these pathways intersect to influence cancer cell phenotypes. A K99/R00 training award will allow me to carry out this transformative project, further developing my current skills in mouse genetics, mRNA translation biology, learn new techniques for in vitro and in vivo ribosome profiling analysis while also allowing me to acquire knowledge in clinical aspects of pancreatic cancer and new expertise in biochemical signaling and integrative systems biology.

项目概要 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 进行有影响力的癌症生物学研究并指导下一代敬业的科学家。我是 对胰腺导管癌症发展和治疗耐药的机制特别感兴趣 腺癌（PDAC）。 PDAC 是最致命的疾病之一，其生存率尚未改善 过去25年里大幅增长。目前对于 PDAC 患者尚无有效的治疗方法。美国国家癌症研究所 (NCI) 在 根据顽固性癌症研究法案，建立了一个科学框架，其中顶级 优先事项是开发靶向疗法和疗法以克服目前的耐药性 可用的代理。我们提出的研究计划通过识别未得到充分认识的非 组蛋白赖氨酸甲基转移酶 METTL10 作为 eEF1A（真核延伸因子 1）的关键调节因子 α) mRNA 翻译机制的基本非核糖体成分。失调 蛋白质的产生是癌症的一个标志，与异常细胞增殖、存活和细胞结构改变有关。 免疫反应和癌症能量学。该 K99/R00 提案的总体目标侧重于 eEF1A 的赖氨酸甲基化调节蛋白质合成速率，这是最消耗能量的 细胞中的过程，并在人类癌症的生长中发挥着关键作用。 目标 1 的目标是阐明 METTL10 在致癌 KRAS 驱动的胰腺癌中的作用。 我们将测试 METTL10 通过其甲基化活性与 KRAS 信号传导合作的假设 使用小鼠胰腺模型促进体内癌细胞无限增殖，其中 KRAS 通路经常被激活。我们还将研究 METTL10 在人体组织中的致瘤作用 使用患者来源的异种移植（PDX）模型。接下来，我们将研究甲基化在特定情况下的作用。 在 PDAC 小鼠模型中使用核糖体分析技术生产蛋白质。最后我们将探讨 METTL10 消融与 MAP 激酶抑制剂在临床前模型中的潜在协同作用 胰腺癌。在目标 2 中，我们将表征 METTL10 的生理催化活性及其 体外调节 eEF1A 活性和细胞内 mRNA 翻译生物学的分子功能。我们将 还研究了 METTL10 和甲基化 eEF1A 相互作用伙伴以及这些途径如何交叉 影响癌细胞表型。 K99/R00 培训奖将使我能够开展这一变革性项目，进一步发展我的能力 小鼠遗传学、mRNA 翻译生物学的现有技能，学习体外和体内新技术 核糖体谱分析，同时也让我获得胰腺癌临床方面的知识 以及生化信号和综合系统生物学方面的新专业知识。

项目成果

SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy.

• DOI: 10.1016/j.ccell.2020.04.014
• 发表时间: 2020-06-08
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Wang Z;Hausmann S;Lyu R;Li TM;Lofgren SM;Flores NM;Fuentes ME;Caporicci M;Yang Z;Meiners MJ;Cheek MA;Howard SA;Zhang L;Elias JE;Kim MP;Maitra A;Wang H;Bassik MC;Keogh MC;Sage J;Gozani O;Mazur PK
• 通讯作者: Mazur PK

Cytoskeleton remodeling induced by SMYD2 methyltransferase drives breast cancer metastasis.

• DOI: 10.1038/s41421-023-00644-x
• 发表时间: 2024-01-31
• 期刊: CELL DISCOVERY
• 影响因子: 33.5
• 作者: Casanova, Alexandre G.;Roth, Gael S.;Hausmann, Simone;Lu, Xiaoyin;Bischoff, Ludivine J. M.;Froeliger, Emilie M.;Belmudes, Lucid;Bourova-Flin, Ekaterina;Flores, Natasha M.;Benitez, Ana Morales;Chasan, Tourkian;Caporicci, Marcello;Vayr, Jessica;Blanchet, Sandrine;Ielasi, Francesco;Rousseaux, Sophie;Hainaut, Pierre;Gozani, Or;Le Romancer, Muriel;Coute, Yohann;Palencia, Andres;Mazur, Pawel K.;Reynoird, Nicolas
• 通讯作者: Reynoird, Nicolas