Identification and functional characterization of metabolic adaptations during melanoma metastasis

 描述（由申请人提供）：转移是导致超过90%的癌症患者死亡的原因，但没有专门针对转移性疾病的治疗方法。目前的许多体外转移模型集中于迁移、侵袭和/或失巢凋亡存活的分子机制，但不能概括体内发生转移的环境的复杂性。相反，在转移的小鼠模型中，很难检查使细胞能够通过转移的每个不同步骤进行的分子机制。由于这些原因，人们对体内转移细胞面临的挑战以及如何克服这些挑战知之甚少。我的建议利用临床相关的黑色素瘤转移模型，患者来源的异种移植免疫功能低下的小鼠，解剖成不同的步骤转移级联。在资助的指导阶段，我将专注于识别特定于转移不同阶段的黑色素瘤细胞的代谢和应激反应信号通路，并在功能上验证其重要性。有了这些见解，我将继续独立研究，重点是在这些瓶颈期间参与的途径的分子细节，以确定可能在治疗转移性疾病中有用的新的治疗靶点。

 DESCRIPTION (provided by applicant): Metastasis is responsible for more than 90% of cancer patient mortality yet there are no therapies that specifically target metastatic disease. Many of the current in vitro models of metastasis focus on the molecular mechanisms of migration, invasion and/or surviving anoikis, but cannot recapitulate the complexity of the environment in which metastasis occurs in vivo. Conversely, in mouse models of metastasis, it has been difficult to examine the molecular mechanisms that enable cells to proceed through each distinct step of metastasis. For these reasons little is known about the challenges facing metastasizing cells in vivo, and how they are overcome. My proposal utilizes a clinically relevant model of melanoma metastasis, patient-derived xenografts in immunocompromised mice, to dissect the metastatic cascade into distinct steps. During the mentored phase of the grant, I will focus on identifying metabolic and stress-response signaling pathways that are specific to melanoma cells at different stages of metastasis, and functionally validate their importance. With these insights, I will continue independent research focusing on the molecular details of the pathways that are engaged during these bottlenecks to identify novel therapeutic targets that may prove useful in treating metastatic disease.