Regulation of glucose metabolism to allow tumor initiation and growth

调节葡萄糖代谢以允许肿瘤发生和生长

基本信息

批准号：
9034555
负责人：
MATTHEW G. VANDER HEIDEN
金额：
$ 29.93万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9034555
关键词：
ATP Synthesis Pathway Alleles Animal Model Biochemical Biochemistry Biomass Cancer Model Cell Proliferation Cells Cellular Metabolic Process Cellular Stress Characteristics Cultured Cells Enzyme Activation Enzymes Exons Genetically Engineered Mouse Glucose Goals Growth Health Human In Vitro Lead Maintenance Malignant Neoplasms Messenger RNA Metabolic Metabolic Pathway Metabolic stress Metabolism Mus Normal Cell Normal tissue morphology Nutrient Patients Play Process Property Protein Isoforms Pyruvate Pyruvate Kinase RNA Splicing Regulation Rest Role Signal Transduction Staging Supporting Cell Techniques Technology Testing Tissues Tumor Biology Warburg Effect Work aerobic glycolysis base cancer cell cancer initiation cancer therapy cell growth enzyme activity experience gene product glucose metabolism glucose uptake human cancer mouse model human tissue implantation improved in vivo insight meetings mouse model neoplastic cell programs rapid growth research study response small molecule success tumor tumor growth tumor initiation tumor metabolism tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Altered glucose metabolism is a characteristic feature of most cancer cells, yet it is still poorly understood. Because altered metabolism represents a fundamental difference that exists between cancer cells and normal cells, targeting metabolism holds great promise for improved cancer therapy. However, success depends on understanding how metabolic regulation provides an advantage for tumor cells in relevant cancer models. Cancer cells require altered metabolism to efficiently incorporate nutrients such as glucose into biomass to support proliferation. Our understanding of how cancer cells meet these metabolic needs is based primarily on studies of cultured cells, and nutrient levels in vitro are significanty different from those experienced by tumor cells in vivo. Furthermore, cell proliferation rates in tumors can be low, particularly under conditions of metabolic stress, and a separate metabolic program from that used to support proliferation is needed for cells to thrive when nutrients are limited. Our long-term objective is to develop a comprehensive understanding of how cell metabolism is altered to support all stages of cancer progression in vivo. The M2 isoform of pyruvate kinase (PKM2) promotes glucose use for anabolic processes and is the pyruvate kinase isoform found in all human tumors described to date. The PKM1 isoform is found in many differentiated tissues and promotes efficient ATP synthesis from available nutrients. Paradoxically, despite increased glucose metabolism in cancers, PKM2 expression is associated with decreased pyruvate kinase enzyme activity, and complete loss of PKM2 can accelerate tumor growth. We aim to use genetically engineered mouse cancer models and small molecule pyruvate kinase activators in combination with biochemical approaches to understand how pyruvate kinase regulates glucose metabolism in tumors. We also aim to understand how this regulation contributes to cancer initiation and progression and any non-glycolytic PKM2 functions that might be important for tumors. In Specific Aim 1, we will take advantage of mice with conditional pyruvate kinase alleles to define the role of PKM1 and PKM2 in tumor initiation, as well as determine how pyruvate kinase isoform expression influences the growth of established tumors. In Specific Aim 2, we will investigate how the different regulatory properties of PKM2 influence glucose metabolism and how this impacts tumor biology. In Specific Aim 3, we will determine how cells continue to metabolize glucose in the absence of pyruvate kinase. Together, these studies will advance our understanding of glycolytic regulation in cancer cells in vivo. They will also inform how best to target glucose metabolism for improved cancer therapy.

描述（由申请人提供）：改变的葡萄糖代谢是大多数癌细胞的特征，但仍然了解不足。由于新陈代谢改变代表了癌细胞和正常细胞之间存在的基本差异，因此靶向新陈代谢对改善癌症治疗具有巨大的希望。但是，成功取决于了解代谢调节如何在相关癌症模型中为肿瘤细胞提供优势。癌细胞需要改变新陈代谢，以有效地融入葡萄糖等营养素中，以支持增殖。我们对癌细胞如何满足这些代谢需求的理解主要基于对培养细胞的研究，并且体外营养水平与体内肿瘤细胞经历的营养水平不同。此外，肿瘤中的细胞增殖率可能很低，尤其是在代谢胁迫的条件下，并且在养分受到限制时，需要与用于支持增殖的单独代谢程序来壮成长。我们的长期目标是对如何改变细胞代谢的方式有一个全面的了解，以支持体内癌症进展的所有阶段。丙酮酸激酶（PKM2）的M2同工型可促进合成代谢过程的葡萄糖用途，并且是迄今为止所有人类肿瘤中发现的丙酮酸激酶同工型。 PKM1同工型在许多分化的组织中发现，并从可用的营养素中促进有效的ATP合成。矛盾的是，尽管癌症中葡萄糖代谢增加，但PKM2表达与丙酮酸激酶活性降低有关，而PKM2的完全丧失可以加速肿瘤的生长。我们的目标是使用基因工程的小鼠癌模型和小分子丙酮酸激酶活化剂与生化方法结合使用，以了解丙酮酸激酶如何调节肿瘤中的葡萄糖代谢。我们还旨在了解该调节如何有助于癌症的启动和进展以及任何可能对肿瘤很重要的非糖酵解PKM2功能。在特定的目标1中，我们将利用有条件丙酮酸激酶等位基因的小鼠来定义PKM1和PKM2在肿瘤起始中的作用，并确定丙酮酸激酶同工型表达如何影响既定肿瘤的生长。在特定目标2中，我们将研究PKM2的不同调节性能如何影响葡萄糖代谢以及这如何影响肿瘤生物学。在特定的目标3中，我们将在没有丙酮酸激酶的情况下确定细胞如何继续代谢葡萄糖。总之，这些研究将提高我们对体内癌细胞糖酵解调节的理解。他们还将告知如何最好地靶向葡萄糖代谢以改善癌症治疗。