Identifying and exploiting metabolic vulnerabilities in cancer using mass spectrometry and tracing approaches

项目总结 代谢重排对癌细胞的生存至关重要，代谢功能障碍重新成为 癌症。然而，我们目前对癌症的代谢途径和调控的了解仍然有限。 质谱学和代谢流分析方面的显著进步极大地提高了我们的能力 量化新陈代谢导致新的治疗策略。通过NCI研究专家奖，我们的目标是 为Thekla Cordes设立一个受保护的职位，为期5年，以支持Christian Metallo教授在 加州大学圣地亚哥分校。Thekla Cordes是一位研究癌症新陈代谢的专家 代谢系统生物学接近并将成为完成当前和未来研究目标的关键人员 NCI资助的研究项目。她的研究旨在识别和利用癌症和癌症中的代谢脆弱性 将主要资助R01CA234245基金“癌症中的非必需氨基酸和鞘磷脂多样性” 进展“。具体地说，她将1)开发和应用基于质谱学的分析方法 量化不同癌症环境中的代谢物水平和代谢通量。她将专注于13C、15N和2H 追踪中心碳、脂和氧化还原代谢的方法。然后她将建立安克雷奇-- 独立的细胞培养模型，以更好地模拟肿瘤环境。此外，她还将设计细胞系。 关注氨基酸(即丝氨酸和丙氨酸)和鞘磷脂的基因改变的代谢途径 代谢(即丝氨酸棕榈酰转氨酶(SPT)。最后，她将把追踪法和培养法结合起来 以深入了解癌症中代谢重编程的生化和机制。我们预计 Thekla Cordes在代谢流方法和途径研究方面的专业知识将提供关键的新见解 并将形成新的令人兴奋的研究方向，影响广泛的癌症领域 生物学。最终，她的支持、科学专业知识和结果有望大幅推动 开发新的和改进的治疗策略来与癌症作斗争。

PROJECT SUMMARY Metabolic rewiring is essential for cancer cell survival and metabolic dysfunction re-emerged as a hallmark for cancer. However, our current knowledge of metabolic pathways and the regulation in cancer is still limited. Striking improvements in mass spectrometry and metabolic flux analysis has greatly improved our ability to quantify metabolism leading to novel treatment strategies. With this NCI Research Specialist Award, we aim to establish a protected position for Thekla Cordes for 5 years to support research for Prof. Christian Metallo at the University of California, San Diego. Thekla Cordes is an expert in dissecting cancer metabolism by applying metabolic systems biology approaches and will be key personnel to complete current and future research goals of NCI-funded research projects. Her research aims to identify and exploit metabolic vulnerabilities in cancer and will mainly support the R01CA234245 grant “Non-essential amino acids and sphingolipid diversity in cancer progression”. Specifically, she will 1) develop and apply mass spectrometry-based analytical approaches to quantify metabolite levels and metabolic fluxes in diverse cancer settings. She will focus on 13C, 15N, and 2H tracing approaches to trace central carbon, lipid, and redox metabolism. She will then 2) establish anchorage- independent cell culture models to better mimic the tumor environment. Further, she will engineer cell lines with genetically altered metabolic pathways focusing on amino acid (i.e. serine and alanine) and sphingolipid metabolism (i.e. serine palmitoyl transaminase (SPT). Finally, she will 3) combine tracer and culture approaches to gain insights into biochemical and mechanistic understanding of metabolic reprograming in cancer. We expect that Thekla Cordes’ expertise in metabolic flux approaches and pathway study will provide critical new insights into cancer metabolism and will nucleate new exciting research directions impacting the broad field of cancer biology. Ultimately, her support, scientific expertise, and results are expected to substantially advance the development of new and improved therapeutic strategies to combat cancer.