Identifying metabolic dependencies in Hurthle cell carcinoma of the thyroid-Res 1

项目总结： 癌症需要新陈代谢适应，以支持推动肿瘤生长的不受控制的增殖。突变 在线粒体基因组(MtDNA)中观察到许多癌症，但这些突变在形成中的作用 细胞代谢和肿瘤生长尚不完全清楚。线粒体DNA突变会损害基因的成分 在大多数形式的癌症中，电子传输链(ETC)似乎是被选中的。Hürthle细胞癌 甲状腺癌(HTC)是一种临床上具有侵袭性的癌症，具有独特的功能缺失突变。 ETC的复合体I的组成部分。我们认为HTC代表了一种理想的疾病异常值 询问线粒体DNA改变等功能在癌症中的作用。在这份提案中，我们采用了独特的 高度互补的方法来表征HTC和其他疾病mtDNA突变的代谢影响 甲状腺癌和肾癌。首先，我们已经开发了一种临床方案来直接监测中枢碳 在外科患者中使用稳定同位素示踪(目标1)。第二，我们发现了一种人工合成的致命相互作用 由复合体I突变编码，并确定了一种有前景的小分子疗法，使用患者来源的 模型(目标2)。最后，我们开发了新的GEMM，从中可以询问复杂I的作用 在甲状腺肿瘤发生中的作用(目标3)。这些方法具有很强的互补性和协同性 每个人都独立地准备弥合关键的知识差距，并对代谢调节产生新的见解 在癌症中。这项提案的总体目标是描述由以下因素所必需的代谢适应 在接受甲状腺手术的患者中，HTC中直接存在的复合体I丢失，以确定和定位代谢责任 作为复合体I丢失下游代谢重排的结果，并确定复合体I丢失是否起作用 促进或改变小鼠甲状腺肿瘤的形成。这些发现将直接和直接地与 甲状腺癌患者，提供了与其他携带mtDNA突变的肿瘤相关的新见解，并具有 通过提供对ETC在癌症中的作用的新见解，对癌症类型的广泛影响。

Project Summary: Cancers require metabolic adaptations to support the unbridled proliferation that drives tumor growth. Mutations in the mitochondrial genome (mtDNA) are observed in many cancers, but the role of these mutations in shaping cellular metabolism and tumor growth is incompletely understood. mtDNA mutations that impair components of the electron transport chain (ETC) appear to be selected against in most forms of cancer. Hürthle cell carcinoma of the thyroid (HTC) is clinically aggressive cancer uniquely enriched for loss-of-function mtDNA mutations in components of complex I of the ETC. We propose that HTC represents an ideal disease outlier in which to interrogate the role of mtDNA alterations and ETC function in cancer. In this proposal, we employ unique and highly complementary approaches to characterize the metabolic impact of mtDNA mutations in HTC and other forms of thyroid and kidney cancer. First, we have developed a clinical protocol to monitor central carbon directly in surgical patients using stable isotope tracing (Aim 1). Second, we have identified a synthetic lethal interaction encoded by complex I mutation and identified a promising small molecule therapeutic using patient-derived models (Aim 2). Finally, we have developed novel GEMMs from which to interrogate the role of complex I function in thyroid tumorigenesis (Aim 3). These approaches are highly complementary and synergistic, yet each is independently poised to bridge key knowledge gaps and lead to new insights into metabolic regulation in cancer. The overall goals of this proposal are to characterize the metabolic adaptations necessitated by complex I loss in HTC directly in patients undergoing thyroid surgery, to identify and target metabolic liabilities as a result of metabolic re-wiring downstream of complex I loss, and to determine whether complex I loss acts to promote or alter thyroid tumor formation in mice. These findings will be of immediate and direct relevance to thyroid cancer patients, provide new insights relevant to other tumors harboring mtDNA mutations and have broad implications across cancer types by providing new insights into ETC function in cancer.