Elucidating SETD2 Loss-Induced Alterations of 3D Chromatin Architecture in Kidney Cancer Metastasis
Abstract
Background: Despite recent advances in kidney cancer treatment, kidney cancer remains the 8th most common cancer with ~63,000 new cases and ~14,000 fatalities each year in the United States alone, devastating patients, their families and friends, and communities, among whom many are current or former military personnel. Renal cell carcinoma (RCC) accounts for > 90% of cancers detected in the kidney, encompassing a large heterogeneous group of cancers derived from renal tubular epithelial cells. Clear cell renal cell carcinoma (ccRCC) is the most common (70%-75% of kidney cancer) and aggressive subtype of kidney cancer. Metastasis is the process by which cancer cells spread to distant locations in the body. The majority of death associated with kidney cancer is due to the metastasis of the original tumor cells. However, how kidney cancers spread to distant locations in the body remains largely unknown. In this grant application, we focus on SETD2, the top three mutated gene in ccRCC that is associated with kidney cancer spreading to distant organs. Our goal is to investigate the mechanisms by which SETD2 mutations promote kidney cancer metastasis. Specifically, we will investigate whether SETD2 mutations alter three-dimensional (3D) genome organization to promote kidney cancer metastasis. Areas of Emphasis: Chromatin and Gene Regulation; Genetics Innovation: The three-dimensional (3D) genome organization plays a critical role in gene regulation, cell fate decisions, and control of cellular function in normal and disease states. Alterations of the 3D genome have emerged as a new hallmark of cancer. However, the 3D chromosome architecture in kidney cancer has not been thoroughly investigated. In this grant application, we have established invaluable experimental models of SETD2-mutated kidney cancer for the study of kidney cancer metastasis. An innovative approach involving advanced sequencing and genome-mapping techniques will be performed to establish the molecular networks of SETD2 with the goal of identifying mechanisms of tumor metastasis and new therapeutic strategies. Overall, this is a mechanism-driven proposal that employs innovative approaches and concepts, which will have broad impact on cancer biology beyond kidney cancer. Impact: SETD2 is not only frequently mutated in kidney cancer but also in a wide variety of human cancers including lung cancer, uterine cancer, bladder cancer, liver cancer, stomach cancer, and colorectal cancer. Despite the recognition of SETD2 as an important tumor suppressor gene, how SETD2 mutations promote tumor formation and metastasis remains unclear. Our investigation of the molecular mechanisms by which SETD2 mutations promote metastasis of kidney cancer will advance the knowledge regarding the biological function of SETD2 as well as the molecular pathogenesis of SETD2-mutated kidney cancer, which will have significant impact now and in the future. In the short term, the knowledge derived from our study can be applied to other human cancers with SETD2 mutations. In the long term, our elucidation of tumor suppressor mechanisms of SETD2 will pave the way for the future discovery of therapeutic strategies for SETD2-mutated cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110814
Entities
People
- Emily Cheng
Organizations
- Sloan-Kettering Institute
- United States Army