Understanding the role of serine metabolism in cancer

 描述(由申请人提供)：新陈代谢改变是肿瘤的一个鲜为人知的特征，它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为肿瘤细胞提供优势。我们对癌细胞如何满足其代谢需求的理解主要基于对培养细胞的研究；体外的营养水平与体内肿瘤细胞经历的营养水平显著不同。因此，迫切需要更好的模型来研究癌症在体内的代谢。最近，一些研究集中在丝氨酸代谢作为癌症中调节失调的一种重要代谢途径。糖酵解分支的丝氨酸合成途径的通量增加对癌细胞增殖和肿瘤生长至关重要，许多关键的代谢调节事件促进了新丝氨酸合成的增加。然而，增加丝氨酸途径的流量对于一些癌细胞来说是必要的，即使在丝氨酸丰富的情况下，为什么增加丝氨酸代谢对癌症来说是重要的还不清楚。编码丝氨酸合成途径第一种酶的基因PHGDH在包括黑色素瘤在内的人类肿瘤中得到扩增，代表了癌细胞从葡萄糖中增加丝氨酸合成的一种方式。通过增加PHGDH酶的表达，可以在细胞中诱导更多的碳流进入丝氨酸合成，这为确定更多的丝氨酸合成是否可能是恶性肿瘤的驱动因素提供了机会。它也为调节丝氨酸合成和研究该途径对肿瘤新陈代谢的影响提供了一个工具。为了更好地理解丝氨酸合成在肿瘤生物学中的作用，我们在目标1中建议建立一个PHGDH扩增的癌症模型。具体地说，我们将使用基因工程小鼠模型，在该模型中，PHGDH的表达可以以时间和组织特异性的方式进行控制，以确定PHGDH表达增加到人类肿瘤中的水平是否会促进肿瘤的启动。对于这些实验，我们将重点放在黑色素瘤上，并评估PHGDH与人类黑色素瘤相关的其他遗传事件合作的能力。通过评估PHGDH表达时形成的肿瘤，我们还将确定PHGDH持续表达和丝氨酸生物合成增加是否是维持肿瘤所必需的。在目标2中，我们建议研究丝氨酸生物合成增加如何影响体内代谢以促进肿瘤生长。我们将跟踪稳定同位素标记的营养物质在黑色素瘤中的代谢情况，以确定这些肿瘤如何利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代谢的影响。这些研究将结合使用独特的动物模型和当前的技术来询问代谢途径生物化学，并增加对体内肿瘤代谢的了解。他们还将验证丝氨酸合成作为抗癌药物的靶点，并帮助努力靶向患者的新陈代谢。

 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.