Identification and functional characterization of metabolic adaptations during melanoma metastasis

 描述(申请人提供)：转移是导致超过90%的癌症患者死亡的原因，但目前还没有专门针对转移疾病的治疗方法。目前的许多体外转移模型主要集中在转移、侵袭和/或存活的分子机制上，但不能概括体内转移发生的复杂环境。相反，在转移的小鼠模型中，很难研究使细胞能够通过每一个不同的转移步骤的分子机制。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。我的建议利用了一种临床相关的黑色素瘤转移模型，即免疫受损小鼠的患者来源的异种移植，将转移级联分解为不同的步骤。在资助的指导阶段，我将专注于识别黑色素瘤细胞在不同转移阶段的代谢和应激反应信号通路，并从功能上验证它们的重要性。有了这些见解，我将继续进行独立研究，重点放在这些瓶颈期间参与的通路的分子细节上，以确定可能被证明对治疗转移性疾病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.