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.

项目总结/摘要 活细胞需要持续不断的营养供应，提供能量和构建模块，以支持 重要的活动和成长。养分供应的波动是不可避免的。因此，为了生存，细胞需要 通过重组新陈代谢来适应这些变化。在低等生物中研究这种代谢适应 彻底改变了我们对生物系统的理解例如，原核生物 对乳糖和葡萄糖作为碳源的可及性变化的反应导致了基因的概念 在鉴定乳糖操纵子后进行调控。 在真核生物中，亚细胞器的进化为生物化学提供了最佳环境。 反应进行。此外，这个系统允许真核细胞进化出额外的策略， 除了通过细胞膜被动扩散或运输外，还能获得营养。从内- 在溶酶体区室中，细胞可以从细胞外大分子中吸收营养，这为它们提供了 具有代谢灵活性，通过平衡其营养成分， 微环境与营养需求的关系。 营养获取策略被恶性细胞充分利用以在严酷的肿瘤中生存 微环境胰腺癌是一种致命的恶性肿瘤，是代谢适应的范例。低- 胰腺导管腺癌（PDAC）的血管化限制了游离营养物和氧气的递送， 癌细胞为了克服营养缺乏，癌症和基质细胞依赖于从细胞内清除营养。 和细胞外大分子分别通过自噬和巨胞饮作用。两种途径汇合 在溶酶体上，溶酶体是一种降解大分子以回收其营养成分的细胞器。 尽管溶酶体在癌症中起着重要作用，但在体内研究高度异质性肿瘤中的溶酶体是非常困难的。 由于缺乏工具，使得溶酶体内容物的功能性分析， 以细胞类型特异性分辨率的肿瘤发生。在这份提案中，我将描述我们的新方法， 一种创新技术，可以快速捕获肿瘤中特定细胞类型的溶酶体， 分析它们的代谢物、脂质和蛋白质含量，以了解恶性和基质细胞中的溶酶体 介导代谢适应。我们还将设计一个模块化的鼠标模型系统， 询问溶酶体对肿瘤微环境中存在的主要代谢应激源的反应。 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亚细胞和细胞类型特异性的前所未有的理解 新陈代谢.我们相信，我们的工作有可能彻底改变我们对代谢的理解， 适应哺乳动物系统，并确定可作为新的治疗利用的脆弱性 胰腺癌的靶点。

项目成果

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

Carnitine octanoyltransferase对于在哺乳动物细胞中将外源性乙酰基-L-肉碱同化成乙酰辅酶A中很重要。

• 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

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.

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