Regulation of glucose metabolism to allow tumor initiation and growth

描述(申请人提供)：葡萄糖代谢改变是大多数癌细胞的特征，但人们对此仍知之甚少。由于新陈代谢的改变代表了癌细胞和正常细胞之间存在的根本差异，靶向新陈代谢为改进癌症治疗带来了巨大的希望。然而，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，才能有效地将葡萄糖等营养物质整合到生物量中，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是基于对培养细胞的研究，体外的营养水平与体内肿瘤细胞所经历的显著不同。此外，肿瘤中的细胞增殖率可能很低，特别是在代谢应激的条件下，需要与用于支持增殖的代谢计划分开，以便在营养有限的情况下细胞蓬勃发展。我们的长期目标是全面了解细胞代谢是如何改变的，以支持体内癌症发展的所有阶段。丙酮酸激酶的M2亚型(PKM2)促进葡萄糖在合成代谢过程中的利用，是迄今为止在所有人类肿瘤中发现的丙酮酸激酶亚型。PKM1亚型在许多分化的组织中被发现，并促进有效的营养物质合成ATP。矛盾的是，尽管癌症中的葡萄糖代谢增加，但PKM2的表达与丙酮酸激酶活性的降低有关，而PKM2的完全缺失可以加速肿瘤的生长。我们的目标是使用基因工程小鼠癌症模型和小分子丙酮酸激酶激活剂，并结合生物化学方法来了解丙酮酸激酶如何调节肿瘤中的葡萄糖代谢。我们的目标也是了解这种调控如何促进癌症的发生和发展，以及任何可能对肿瘤重要的非糖酵解PKM2功能。在特定的目标1中，我们将利用具有条件性丙酮酸激酶等位基因的小鼠来确定PKM1和PKM2在肿瘤启动中的作用，以及丙酮酸激酶亚型的表达如何影响已建立的肿瘤的生长。在特定的目标2中，我们将研究PKM2的不同调节特性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，我们将确定细胞如何在没有丙酮酸激酶的情况下继续代谢葡萄糖。总之，这些研究将促进我们对体内癌细胞糖酵解调节的理解。他们还将介绍如何最好地针对葡萄糖代谢来改进癌症治疗。

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.