Cancer Center Support Grant

抽象的。 本申请是为了回应被确认为非CA-CA的特殊利益通知(NOSI)而提交的 21比100。 器官趋向性是指转移性癌细胞对特定器官的亲和力。在表现出高水平的癌症中 器官嗜好的程度是葡萄膜黑色素瘤(UM)，这是成年人最常见的眼内恶性肿瘤。嗯，有 一种明显的肝转移倾向，肝转移患者预后最差。 中位生存期不到12个月。UM倾向于传播到 肝脏是未知的，但对我们预防和治疗转移性UM的能力至关重要，目的是延长 病人存活率。作为一名眼科医生，我能够从UM患者身上获取眼球摘除标本， 并进行单细胞RNA测序，然后进行生化和功能分析。这使我们能够 发现低转移倾向和高转移倾向的UM不是根本不同的疾病亚型； 更确切地说，原发肿瘤有不同转移倾向的亚克隆。我们发现丢失了一把钥匙 表观遗传调节因子，多梳抑制复合体1(Prc1)，诱导了从惰性到 侵袭性UM表型。在分析转移标本的遗传特征时，我发现UM 肝内转移瘤与肝外转移瘤相比，基因组特征不同，预后更差。 转移瘤。这项建议旨在确定转移性UM向肝脏的分子基础。 我将测试葡萄膜黑色素瘤扩散到肝脏的假设是由先前存在的 原发肿瘤中由Prc1缺失驱动的表型。在目标1下，我将采用单一电池 用基因组学方法研究肝脏肿瘤内和肝外转移的异质性。在目标2下， 我将在可移植的小鼠模型中测试PRC1缺失是否选择性地促进UM肝转移 恩。通过整合来自临床标本的基因组数据和临床前模型中的功能验证，这 这项工作旨在了解转移性UM器官趋向性的分子基础。我是一名助理 在我被任命为终身教职的第一年，我就成了耶鲁大学医学院的教授。我有过 两位杰出的导师。马库斯·博森伯格博士是一位临床科学家，在培训方面有丰富的记录。 博士后研究员和内科科学家，并将为我提供额外的老鼠建模培训。 Mario Sznol博士是一位肿瘤学家，专门研究转移性黑色素瘤患者的治疗。 他们将为我提供指导和支持，最终实现完全的科学独立。我的 有组织的培训和职业发展计划包括老鼠建模和科学写作方面的课程， 在全国会议上发表演讲，并定期与我的导师安排职业发展会议。我的 临床和外科实践将使我能够确定管理病人的挑战和需要的领域 与UM。总的来说，这种培训环境将为我提供额外和必要的培训，并将 帮助我实现建立一个由NIH资助的实验室的目标。

ABSTRACT. This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 21-100. Organotropism is the affinity of metastatic cancer cells for specific organs. Among cancers that exhibit high degree of organotropism is uveal melanoma (UM), the most common intraocular malignancy in adults. UM has a conspicuous predilection to spread to the liver, and patients with liver metastases have the worst prognosis with a median survival less than 12 months. The mechanisms underlying the proclivity of UM to spread to the liver are unknown, yet are critical to our ability to prevent and treat metastatic UM with the aim of prolonging patient survival. As an ophthalmic surgeon, I was able to obtain enucleation specimens from patients with UM, and perform single-cell RNA sequencing, followed by biochemical and functional analyses. This enabled us to discover that UMs with low and high metastatic tendencies are not fundamentally distinct disease subtypes; rather primary tumors harbor subclones with different metastatic proclivities. We identified that loss of a key epigenetic regulator, Polycomb Repressive Complex 1 (PRC1), induced a transition from an indolent to an aggressive UM phenotype. While analyzing the genetic characteristics of metastatic specimens, I found that UM metastases in the liver have a different genomic profile, and worse prognosis, than those with extrahepatic metastases. This proposal aims to determine the molecular underpinnings of metastatic UM tropism to the liver. I will test the hypothesis that the spread of uveal melanoma to the liver is dictated by a pre-existing distinct phenotype in the primary tumor which is driven by loss of PRC1. Under Aim 1, I will employ single cell genomics to characterize intratumor heterogeneity in hepatic as well as extra-hepatic metastases. Under Aim 2, I will test whether loss of PRC1selectively promotes UM liver metastasis in transplantable mouse models of UM. By integrating genomic data from clinical specimens and functional validation in pre-clinical models, this work aims to understand the molecular basis underlying organotropism in metastatic UM. I am an Assistant Professor at Yale University School of Medicine within the first year of my tenure-track appointment. I have two outstanding mentors. Dr. Marcus Bosenberg is a clinician scientist with an extensive track record in training postdoctoral fellows and physician-scientists and will provide me with additional training in mouse modeling. Dr. Mario Sznol is an oncologist who specializes in the management of patients with metastatic melanoma. They will provide me with the mentorship and support to ultimately attain full scientific independence. My structured training and career development plans include coursework in mouse modelling and scientific writing, presentations at national meetings, and regularly scheduled career development meetings with my mentors. My clinical and surgical practice will enable me to identify the challenges and areas of needs in managing patients with UM. Collectively, this training environment will equip me with additional and necessary training and will help me achieve my goal of establishing a NIH-funded laboratory.