Understanding the role of serine metabolism in cancer

了解丝氨酸代谢在癌症中的作用

基本信息

批准号：
9098649
负责人：
MATTHEW G. VANDER HEIDEN
金额：
$ 16.85万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9098649
关键词：
Affect Amino Acids Anabolism Animal Model Antineoplastic Agents Biochemistry Biomass Cancer Model Carbon Cell Proliferation Cells Cellular Metabolic Process Critical Pathways Cultured Cells Drug Targeting Enzymes Event Genes Genetically Engineered Mouse Glucose Glycolysis Goals Growth Health Human In Vitro Lipids Maintenance Malignant Neoplasms Metabolic Metabolic Pathway Metabolism Modeling Mus Normal Cell Nucleic Acids Nutrient Other Genetics Pathway interactions Patients Production Protein Biosynthesis Regulation Role Serine Serum Stable Isotope Labeling Technology Testing Tissues Tumor Biology Work animal tissue base cancer cell cancer therapy chemotherapy experience glucose production improved in vivo interest meetings melanocyte melanoma mouse model neoplastic cell novel anticancer drug overexpression research study success targeted cancer therapy tool tumor tumor growth tumor initiation tumor metabolism tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Altered metabolism is a poorly understood feature of tumors that holds great promise for improved cancer therapy. However, success depends on understanding how metabolic regulation provides an advantage for tumor cells. Our understanding of how cancer cells meet their metabolic needs is based primarily on studies of cultured cells; and nutrient levels in vitro are significantly different from those experienced by tumor cells in vivo. Therefore, better models to study cancer metabolism in vivo are desperately needed. Recently, several studies have converged on serine metabolism as an important metabolic pathway that is dysregulated in cancer. Increased flux through the serine synthesis pathway branching from glycolysis is critical for cancer cell proliferation and tumor growth, and many key metabolic regulatory events promote an increase in new serine synthesis. However, increased serine pathway flux is necessary for some cancer cells even when serine is abundant, and why increased serine metabolism is important for cancer is not understood. The gene encoding the first enzyme of the serine synthesis pathway, PHGDH, is amplified in human tumors, including melanoma, and represents a way cancer cells increase serine production from glucose. Increased carbon flux into serine synthesis can be induced in cells by increasing PHGDH enzyme expression, and this presents the opportunity to determine if more serine synthesis can be a driver of malignancy. It also provides a tool to modulate serine synthesis and study the impact of this pathway on tumor metabolism. To better understand the role of serine synthesis in tumor biology, we propose in Aim 1 to generate a model of PHGDH-amplified cancer. Specifically, we will use a genetically engineered mouse model where PHGDH expression can be controlled in a temporal and tissue-specific manner to determine if increased PHGDH expression to levels found in human tumors promotes tumor initiation. For these experiments we will focus on melanoma, and evaluate the ability of PHGDH to cooperate with other genetic events associated with melanoma in humans. By evaluating tumors that form when PHGDH is expressed, we will also determine whether continued PHGDH expression and increased serine biosynthesis is required for tumor maintenance. In Aim 2, we propose to study how increased serine biosynthesis influences metabolism to promote tumor growth in vivo. We will track the metabolism of stable isotope labeled nutrients in melanomas with and without PHGDH expression to determine how glucose-derived serine is used by these tumors, and understand the impact of increased serine biosynthesis on cancer metabolism. These studies will combine the use of unique animal models with current technology to interrogate metabolic pathway biochemistry and increase the understanding of tumor metabolism in vivo. They will also validate serine synthesis as a cancer drug target and aid efforts to target metabolism in patients.

描述（由申请人提供）：代谢改变是肿瘤的一个鲜为人知的特征，但它对于改善癌症治疗具有很大的希望。然而，成功取决于了解代谢调节如何为肿瘤细胞提供优势。我们对癌细胞如何满足其代谢的理解。需要主要基于对培养细胞的研究；并且体外的营养水平与体内肿瘤细胞经历的营养水平显着不同，因此迫切需要更好的模型来研究体内的癌症代谢。作为重要的代谢途径然而，在癌症中，通过糖酵解分支的丝氨酸合成途径的通量增加对于癌细胞增殖和肿瘤生长至关重要，并且许多关键的代谢调节事件促进新丝氨酸合成的增加。即使丝氨酸丰富，也会产生癌细胞；为什么丝氨酸代谢增加对癌症很重要，编码丝氨酸合成途径第一种酶 PHGDH 的基因在包括黑色素瘤在内的人类肿瘤中被扩增，并且代表了癌细胞的一种方式。增加通过增加 PHGDH 酶的表达，可以诱导细胞中丝氨酸合成的碳通量增加，这为确定更多的丝氨酸合成是否是恶性肿瘤的驱动因素提供了机会。研究该途径对肿瘤代谢的影响为了更好地了解丝氨酸合成在肿瘤生物学中的作用，我们在目标 1 中建议专门生成 PHGDH 扩增的癌症模型，我们将使用基因工程小鼠模型，其中可以以时间和组织特异性的方式控制 PHGDH 表达，以确定 PHGDH 表达增加至人类肿瘤中的水平是否会促进肿瘤发生。对于这些实验，我们将重点关注黑色素瘤，并评估 PHGDH 与其他遗传事件配合的能力。通过评估 PHGDH 表达时形成的肿瘤，我们还将确定肿瘤维持是否需要持续的 PHGDH 表达和增加的丝氨酸生物合成。在目标 2 中，我们建议研究如何增加丝氨酸。我们将追踪有或没有 PHGDH 表达的黑色素瘤中稳定同位素标记的营养物质的代谢，以确定这些肿瘤如何使用葡萄糖衍生的丝氨酸，并了解丝氨酸生物合成增加对癌症的影响。这些研究将结合使用独特的动物模型和现有技术来探究代谢途径的生物化学，并增加对体内肿瘤代谢的理解，它们还将验证丝氨酸合成作为癌症药物靶点并帮助努力。以患者的新陈代谢为目标。