Innovations and mechanisms in tumor subcellular metabolism

肿瘤亚细胞代谢的创新与机制

• 批准号: 10244785
• 负责人: Monther Abu-Remaileh
• 金额: $ 141.62万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10244785
• 关键词: Autophagocytosis; Biochemical Reaction; Biological Models; Carbon; Cell membrane; Cells; Diffusion; Environment; Equilibrium; Eukaryota; Eukaryotic Cell; Evolution; Gene Expression Regulation; Genetic; Glucose; Growth; Human; Lac Operon; Lactose; Lipids; Lower Organism; Lysosomes; Malignant Neoplasms; Malignant Stromal Cell; Malignant neoplasm of pancreas; Mediating; Metabolic; Metabolism; Molecular; Nutrient; Organelles; Oxygen; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Prokaryotic Cells; Proteins; Resolution; Role; Source; Stromal Cells; System; Vascularization; Work; biological systems; cancer cell; cell type; design; extracellular; flexibility; in vivo; innovation; innovative technologies; macromolecule; metabolic abnormality assessment; mouse model; new therapeutic target; novel strategies; response; stressor; tool; tumor; tumor metabolism; tumor microenvironment; tumorigenesis

Project Summary/Abstract Living cells require a constant supply of nutrients that provide energy and building blocks to support their vital activities and growth. Fluctuations in nutrient availability are inevitable. Thus, to survive, cells need to adapt to these changes by rewiring their metabolism. Studying this metabolic adaptation in lower organisms has revolutionized our understanding of biological systems. For example, the discovery of how prokaryotes respond to changes in the accessibility to lactose and glucose as a carbon source led to the concept of gene regulation after the identification of the lac operon. In eukaryotes the evolution of subcellular organelles provided an optimal environment for biochemical reactions to proceed. Moreover, this system allowed the eukaryotic cell to evolve additional strategies to acquire nutrients besides passive diffusion or transport across the cell membrane. Through the endo- lysosomal compartment, cells can scavenge nutrients from extracellular macromolecules, which provides them with metabolic flexibility to survive various states of nutrient availability by balancing the composition of their microenvironment with their nutrient demands. Nutrient acquisition strategies are fully exploited by malignant cells to survive the harsh tumor microenvironment. Pancreatic cancer, a lethal malignancy, is a paradigm of metabolic adaptation. Hypo- vascularization of pancreatic ductal adenocarcinoma (PDAC) limits the delivery of free nutrients and oxygen to cancer cells. To overcome nutrient scarcity, cancer and stromal cells rely on scavenging nutrients from intra- and extracellular macromolecules via autophagy and macropinocytosis, respectively. Both pathways converge on the lysosome, a cellular organelle that degrades macromolecules to recycle their nutrient content. Despite their essential role in cancer, studying lysosomes in highly heterogenous tumors in vivo is challenging because of the lack of tools that allow the functional profiling of lysosomal content during tumorigenesis at a cell-type-specific resolution. In this proposal, I will describe our novel approach to develop an innovative technology that allows the rapid capturing of lysosomes from specific cell types in the tumor to profile their metabolite, lipid and protein contents to understand how lysosomes in malignant and stromal cells mediate metabolic adaptation. We will also design a modular mouse model system that will allow the selective interrogation of the lysosomal response to major metabolic stressors that exist in the tumor microenvironment. Our innovative approaches combined with functional characterization of the lysosomal components using genetic tools will result in an unprecedent subcellular and cell-type-specific understanding of tumor metabolism. We believe that our work has the potential to revolutionize our understanding of metabolic adaptation in mammalian systems, and to identify vulnerabilities that can be exploited as novel therapeutic targets in pancreatic cancer.

项目摘要/摘要 活细胞需要持续的营养供应，以提供能量和构建块以支撑 他们的重要活动和成长。营养利用率的波动是不可避免的。因此，为了生存，细胞需要 通过重新将它们的新陈代谢改编来适应这些变化。在较低的生物体中研究这种代谢适应 已经彻底改变了我们对生物系统的理解。例如，发现原核生物如何 响应乳糖和葡萄糖作为碳源的可及性的变化导致了基因的概念 识别LAC操纵子后的调节。 在真核生物中，亚细胞细胞器的演变为生化提供了最佳的环境 进行的反应。此外，该系统允许真核细胞发展其他策略 除了被动扩散或在细胞膜上运输外，还获得了营养。通过endo- 溶酶体室，细胞可以从细胞外大分子中清除营养，从而提供它们 具有代谢灵活性，可以通过平衡其成分来生存各种养分状态 微环境符合其营养需求。 恶性细胞充分利用营养的获取策略，以在恶劣的肿瘤中生存 微环境。胰腺癌是一种致命的恶性肿瘤，是代谢适应性的范式。低 胰腺导管腺癌（PDAC）的血管化限制了游离养分和氧气的递送 癌细胞。为了克服养分稀缺性，癌症和基质细胞依赖于从内部清除营养 分别通过自噬和大型细胞增多症和细胞外大分子。两种途径都融合 在溶酶体上，一种降解大分子以回收其养分含量的细胞细胞器。 尽管它们在癌症中起着至关重要的作用，但研究在体内高度异源肿瘤中的溶酶体是 具有挑战性，因为缺乏允许溶酶体含量功能分析的工具 细胞类型特异性分辨率的肿瘤发生。在此提案中，我将描述我们发展的新方法 一种创新的技术，可快速捕获从肿瘤中特定细胞类型到的溶酶体到 介绍其代谢产物，脂质和蛋白质含量，以了解恶性和基质细胞中的溶酶体如何 介导代谢适应。我们还将设计一个模块化鼠标模型系统，该系统将允许选择性 对肿瘤微环境中存在的主要代谢胁迫的溶酶体反应的询问。 我们的创新方法结合了溶酶体成分的功能表征 使用遗传工具将导致对肿瘤的前所未有的亚细胞和细胞类型的理解 代谢。我们认为，我们的工作有可能彻底改变我们对代谢的理解 在哺乳动物系统中适应，并确定可以被用作新型治疗的漏洞 胰腺癌的靶标。

项目成果

Carnitine octanoyltransferase is important for the assimilation of exogenous acetyl-L-carnitine into acetyl-CoA in mammalian cells.

• DOI: 10.1016/j.jbc.2022.102848
• 发表时间: 2023-03
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Hsu, Jake;Fatuzzo, Nina;Weng, Nielson;Michno, Wojciech;Dong, Wentao;Kienle, Maryline;Dai, Yuqin;Pasca, Anca;Abu-Remaileh, Monther;Rasgon, Natalie;Bigio, Benedetta;Nasca, Carla;Khosla, Chaitan
• 通讯作者: Khosla, Chaitan

An SPNS1-dependent lysosomal lipid transport pathway that enables cell survival under choline limitation.

• DOI: 10.1126/sciadv.adf8966
• 发表时间: 2023-04-21
• 期刊: SCIENCE ADVANCES
• 影响因子: 13.6
• 作者: Scharenberg, Samantha G.;Dong, Wentao;Ghoochani, Ali;Nyame, Kwamina;Levin-Konigsberg, Roni;Krishnan, Aswini R.;Rawat, Eshaan S.;Spees, Kaitlyn;Bassik, Michael C.;Abu-Remaileh, Monther
• 通讯作者: Abu-Remaileh, Monther

Isotope tracing in health and disease.

• DOI: 10.1016/j.copbio.2022.102739
• 发表时间: 2022-08
• 期刊: Current opinion in biotechnology
• 影响因子: 7.7

CYP4F2 is a human-specific determinant of circulating N-acyl amino acid levels.

• DOI: 10.1016/j.jbc.2023.104764
• 发表时间: 2023-06
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Tanzo, Julia T.;Li, Veronica L.;Wiggenhorn, Amanda L.;Moya-Garzon, Maria Dolores;Wei, Wei;Lyu, Xuchao;Dong, Wentao;Tahir, Usman A.;Chen, Zsu-Zsu;Cruz, Daniel E.;Deng, Shuliang;Shi, Xu;Zheng, Shuning;Guo, Yan;Sims, Mario;Abu-Remaileh, Monther;Wilson, James G.;Gerszten, Robert E.;Long, Jonathan Z.;Benson, Mark D.
• 通讯作者: Benson, Mark D.