Investigating the molecular mechanisms of growth in GNAS mutant pancreatic cancer.

研究 GNAS 突变型胰腺癌生长的分子机制。

• 批准号: 10666643
• 负责人: Krushna Chandra Patra
• 金额: $ 36.32万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666643
• 关键词: Animal Cancer Model; Animals; Biochemical Pathway; Bioenergetics; Biology; Branched-Chain Amino Acids; CREB1 gene; Cancer Etiology; Cell Line; Cells; Cessation of life; Citric Acid Cycle; Colon; Complex; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Dependence; Detection; Disease; Doxycycline; Enzymes; Fatty Acids; Foundations; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Gene Expression; Genes; Genetic; Genetic Engineering; Genetic Transcription; Genetically Engineered Mouse; Genotype; Gnas protein; Goals; Growth; Heterogeneity; Histologic; Human; Intestines; KRAS oncogenesis; KRAS2 gene; Label; Lesion; Lipids; Maintenance; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metabolic; Metabolic Pathway; Methods; Microscopy; Mitochondria; Modeling; Molecular; Molecular Profiling; Mucinous; Mucinous Neoplasm; Multienzyme Complexes; Mus; Mutate; Mutation; NADH; Neoplasms; Nuclear Translocation; Oncogenic; Organoids; Other Genetics; Oxidative Phosphorylation; Oxidoreductase; Pancreas; Pancreatic Ductal Adenocarcinoma; Papillary; Pathway interactions; Phosphorylation; Pituitary Gland; Proliferating; Protein Isoforms; Publishing; Recurrence; Regulation; Research; Respiration; Role; Sampling; Series; Signal Transduction; Source; Specimen; Stomach; System; TP53 gene; Transcription Coactivator; Transcriptional Activation; Tumor Suppressor Proteins; United States; Up-Regulation; Work; biliary tract; cancer cell; clinically relevant; fatty acid oxidation; gain of function mutation; improved; inhibitor; metabolic phenotype; mouse model; mutant; novel; pancreatic cancer patients; pancreatic neoplasm; patient derived xenograft model; pre-clinical; prevent; programs; protein activation; respiratory; restraint; salt-inducible kinase; tool; transcriptomics; treatment response; treatment strategy; tumor; tumor growth; tumor progression

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer death in the United States with five-year survival after detection is less than 10%. The subset of PDA arises from Intraductal papillary mucinous neoplasm (IPMNs) precursor lesions are distinguished by recurrent activating mutations in GNAS, that encodes G-protein Gαs, and induces cyclic-AMP (cAMP) signaling. GNAS is mutationally activated and amplified pancreatic and many other human tumors, yet its oncogenic functions remain unclear. Therefore, understanding the function of mutant GNAS will provide disease mechanisms and give opportunities to treat PDA even in their early stages. To understand the function of oncogenic GNAS we established a doxycycline-tunable mouse model and showed that mutant GNAS cooperates with oncogenic KRAS to initiate IPMNs that progress to invasive PDA upon p53 loss. GNAS remains critical for the maintenance of established tumors, via a protein kinase A (PKA)-dependent network and resulting inhibition of salt-inducible kinases (SIK1-3). We demonstrated that this network prominently reprograms metabolic pathways which are potential alternative sources of TCA cycle metabolites, respiratory substrates (NADH) and fatty acid intermediates that can support the growth of GNAS mutant tumors. Importantly, GNAS-mutant cancer cells are specifically sensitive to the inhibition of these pathways compared to GNAS-wt tumors. These results establish mutant GNAS as a novel tumor maintenance driver, uncover the underlying PKA-dependent program, establish SIKs as major tumor suppressors, and demonstrate unanticipated metabolic heterogeneity fueling subsets of pancreatic cancer. Based on our published and unpublished supporting data, the overarching goal of this proposal is to understand the roles of critical downstream targets of GNAS-PKA signaling that control the expression of proliferation and metabolic genes. Our research will also illuminate how mutant GNAS regulated expression of a keto dehydrogenase generate biosynthetic and bioenergetic intermediates to support tumor growth. Finally, our study will interrogate the regulation of respiratory activity and its requirement in GNAS mutant pancreatic cancer. This study will leverage advanced methods and unique tools, including global transcriptomic analysis and isotopomer-based metabolic profiling in genetically defined mouse and human organoid systems, preclinical pancreatic cancer animal models, relevant patient-derived xenograft systems and primary samples. Our research will provide understanding of the unique biology of mutant GNAS and points out targetable vulnerabilities in genetic subsets of pancreatic tumors.

项目摘要 胰腺导管腺癌（PDA）是美国癌症死亡的第四个主要原因 检测后的五年生存率小于10％。 PDA的子集来自导管内乳头状粘液 肿瘤（IPMN）前体病变通过GNA中的复发激活突变来区分，该突变是编码的 G蛋白GαS，并诱导环状AMP（CAMP）信号传导。 GNA是突变激活和放大器的 胰腺和许多其他人类肿瘤，但其致癌功能尚不清楚。因此，理解 突变GNA的功能将提供疾病机制，并为治疗PDA提供机会 早期阶段。为了了解致癌GNA的功能，我们建立了一种强力霉素可调的小鼠模型 并表明突变GNA与致癌KRAS合作，以启动发展为侵入性的IPMN P53损失时PDA。 GNA对于通过蛋白激酶A维持已建立的肿瘤仍然至关重要 （PKA）依赖性网络，并抑制盐诱导激酶（SIK1-3）。我们证明了这一点 网络突出地重新编程代谢途径，这是TCA循环的潜在替代来源 代谢物，呼吸底物（NADH）和脂肪酸中间体可以支持GNA的生长 突变肿瘤。重要的是，GNA突变癌细胞对抑制特异性敏感 与GNAS-WT肿瘤相比。这些结果将突变GNA作为一种新型的肿瘤维持 驾驶员，发现基本的依赖PKA的程序，将锡克斯建立为主要肿瘤补充剂，并且 证明意外的代谢异质性加油胰腺癌子集。基于我们 该提案的总体目标是发布和未发表的支持数据，是了解 控制增殖和代谢表达的GNAS-PKA信号的临界下游靶标 基因。我们的研究还将阐明突变GNA如何调节酮脱氢酶的表达 产生生物合成和生物能中间体以支持肿瘤生长。最后，我们的研究将询问 调节呼吸活性及其在GNA突变胰腺癌中的需求。这项研究会 利用高级方法和独特的工具，包括全球转录组分析和基于同位素的分析 一般定义的小鼠和人体器官系统中的代谢分析，临床前胰腺癌 动物模型，相关的患者衍生的定义系统和主要样本。我们的研究将提供 了解突变GNA的独特生物学，并指出遗传子集中的可靶向漏洞 胰腺肿瘤。