Cancer Center Support Grant

摘要。 本申请是为了响应被标识为NOT-CA的特别利益通知（NOSI）而提交的- 21-100. 向器官性是转移性癌细胞对特定器官的亲和力。在癌症中， 葡萄膜黑色素瘤（UM）是成人中最常见的眼内恶性肿瘤。嗯有 明显倾向于扩散到肝脏，肝转移患者的预后最差 中位生存期不到12个月UM倾向于扩散到 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 患者生存率。作为一名眼科医生，我能够从UM患者身上获得眼球摘除标本， 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 发现具有低和高转移倾向的UM不是根本不同的疾病亚型; 而原发性肿瘤具有不同转移倾向的亚克隆。我们发现丢失钥匙 表观遗传调节因子Polycomb Repressive Complex 1（PRC 1）诱导了从惰性到惰性的转变。 侵袭性UM表型。在分析转移性标本的遗传特征时，我发现UM 与肝外转移相比，肝内转移具有不同的基因组特征， 转移该建议旨在确定转移性UM向肝嗜性的分子基础。 我将检验葡萄膜黑色素瘤扩散到肝脏是由预先存在的明显的 在原发性肿瘤中，这是由PRC 1的缺失驱动的。根据目标1，我将采用单细胞 基因组学来表征肝转移瘤和肝外转移瘤中的瘤内异质性。根据目标2， 我将在可移植的小鼠模型中测试PRC 1的缺失是否选择性地促进UM肝转移。 嗯.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， 这项工作旨在了解转移性UM中向器官性的分子基础。我是助理 在我获得终身教职的第一年，我就成为了耶鲁大学医学院的教授。我有 两位杰出的导师Marcus Bosenberg博士是一位临床科学家，在培训方面有着广泛的记录 博士后研究员和医生科学家，并将为我提供额外的培训，在小鼠建模。 博士Mario Sznol是一名肿瘤学家，专门从事转移性黑色素瘤患者的管理。 他们将为我提供指导和支持，最终实现完全的科学独立。我 结构化培训和职业发展计划包括老鼠建模和科学写作课程， 在国家会议上做演讲，并定期与我的导师举行职业发展会议。我 临床和外科实践将使我能够确定管理患者的挑战和需求领域 在UM。总的来说，这种培训环境将使我获得额外和必要的培训， 帮助我实现建立NIH资助实验室的目标。

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.