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.

项目总结

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