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.

项目概要 胰腺导管腺癌 (PDA) 是美国第四大癌症死亡原因 检测后五年生存率低于 10% PDA 源自导管内乳头状粘液性病变。 肿瘤 (IPMN) 前驱病变的特征是 GNAS 中反复激活的突变，编码 G 蛋白 Gαs，并诱导环 AMP (cAMP) 信号传导被突变激活和放大。 胰腺癌和许多其他人类肿瘤，但其致癌功能仍不清楚。 突变 GNAS 的功能将提供疾病机制，并为治疗 PDA 提供机会，即使在其 为了了解致癌 GNAS 的功能，我们建立了强力霉素可调小鼠模型。 并表明突变的 GNAS 与致癌 KRAS 合作启动 IPMN，从而进展为侵袭性 p53 丢失后的 PDA 对于通过蛋白激酶 A 维持已形成的肿瘤仍然至关重要。 (PKA) 依赖性网络以及由此产生的盐诱导激酶 (SIK1-3) 的抑制。 网络显着地重新编程代谢途径，这是 TCA 循环的潜在替代来源 可支持 GNAS 生长的代谢物、呼吸底物 (NADH) 和脂肪酸中间体 重要的是，GNAS 突变的癌细胞对这些物质的抑制特别敏感。 与 GNAS-wt 肿瘤相比，这些结果表明突变型 GNAS 是一种新的肿瘤维持方法。 驱动程序，揭示潜在的 PKA 依赖性程序，将 SIK 确立为主要的肿瘤抑制因子，以及 根据我们的研究，证明了意想不到的代谢异质性促进了胰腺癌的发生。 已发表和未发表的支持数据，该提案的总体目标是了解 GNAS-PKA 信号传导的关键下游靶标，控制增殖和代谢的表达 我们的研究还将阐明突变体 GNAS 如何调节酮脱氢酶的表达。 最后，我们的研究将探讨如何产生生物合成和生物能中间体来支持肿瘤生长。 本研究将探讨 GNAS 突变型胰腺癌中呼吸活动的调节及其需求。 利用先进的方法和独特的工具，包括全局转录组分析和基于同位素异构体的分析 基因定义的小鼠和人类类器官系统的代谢分析、临床前胰腺癌 我们的研究将提供动物模型、相关的患者来源的异种移植系统和原始样本。 了解突变 GNAS 的独特生物学并指出遗传子集中的可针对的漏洞 胰腺肿瘤。