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Mechanism of LSD1 in breast cancer metastasis suppression

LSD1抑制乳腺癌转移的机制

基本信息

批准号：
10533313
负责人：
Zhe Li
金额：
$ 37.29万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10533313
关键词：
Ablation Address Adhesions Breast Breast Cancer Cell Breast Cancer cell line Breast Epithelial Cells Breast cancer metastasis CDH1 gene CRISPR screen Cell Adhesion Cell Cycle Cell Differentiation process Cell-Cell Adhesion Cells Cessation of life Complex DNA Sequence Alteration Data Deletion Mutation Development Disease EZH2 gene Endogenous Retroviruses Epigenetic Process Estrogen Receptors Estrogen receptor positive Exhibits Failure GATA3 gene Gene Mutation Genes Genetic Models Genetic Transcription Genetic study Genome Genomics Heritability Histone H2A Histones Human Immune Immune response Impairment Injections Invaded KDM1A gene KLRD1 gene Knowledge Ligands Lysine Malignant Neoplasms Mammary Neoplasms Maps Mediating Mediator Metastasis Suppression Metastatic Neoplasm to the Lung Metastatic breast cancer Modeling Molecular Molecular Abnormality Monoubiquitination Mouse Mammary Tumor Virus Mus Mutation Natural Killer Cells Neoplasm Metastasis Oncogenic Oncoproteins Organ Pathway interactions Patients Play Point Mutation Polycomb Primary Neoplasm Proliferating Qa-1 Antigen Regulation Repression Role Scientist Specificity System Testing The Cancer Genome Atlas Translating Up-Regulation Work cancer genome cancer initiation cancer type cell type driver mutation epigenetic regulation gene repression genetic approach genome sequencing histone demethylase in vivo inhibitor malignant breast neoplasm methyl group migration mortality mouse model neoplastic cell new therapeutic target non-genetic novel strategies polyoma middle tumor antigen prevent programs protein complex receptor targeted treatment transcription factor transplant model tumor microenvironment tumor-immune system interactions ubiquitin ligase

项目摘要

Comparisons of genetic mutations found in primary tumors and their corresponding metastatic lesions have so far failed to define genetic mutations that lead to metastasis. This raises a notion that it is the epigenetic mechanisms, working together with cancer type-specific oncogenic and/or cell type-specific lineage programs, that may drive metastatic progression. In breast cancer, how epigenetic abnormalities drive metastatic progression remains largely elusive. A better understanding of this may lead to novel strategies to block breast cancer metastasis. LSD1 (KDM1A) is the first identified histone demethylase. In human cancers, genetic abnormalities of LSD1 mainly include deletions and mutations. Such deletions/mutations have also been found in metastatic breast cancer, raising a possibility that LSD1 is a breast cancer metastasis suppressor. Indeed, in preliminary studies, we found induced loss of LSD1 in luminal mammary tumor cells or LSD1 inhibitor treatment in the MMTV-PyMT mouse model led to a dramatic increase in lung metastasis. Mechanistically, in luminal breast cells, we found LSD1 interacts with GATA3, a key luminal-specific transcription factor, to control their common programs related to cell-cell adhesion and cell cycle. LSD1 positively regulates GATA3 expression and represses that of TRIM37, a common target of both LSD1 and GATA3, which encodes a histone H2A ubiquitin ligase involved in gene repression. Importantly, TRIM37 may contribute to increased invasion and migration of luminal breast cancer cells with LSD1-loss via repression of several cell adhesion genes (e.g., CDH1, VCL, CTNNA1). Such expression changes were also observed in murine PyMT tumor cells with LSD1-loss. Together, these data suggest that LSD1 may suppress breast cancer metastasis via regulation of its target genes (e.g., TRIM37) in luminal cells in a demethylase activity- dependent manner. Intriguingly, PyMT tumor cells with LSD1 ablation also exhibited a profound change in immune-related genes, suggesting that LSD1 may also suppress breast cancer metastasis by a cell-extrinsic, immune-related mechanism. To test these, we will continue to establish mouse intraductal injection (MIND) transplantation models for PyMT tumor cells and human estrogen receptor+ breast cancer cell lines as our in vivo system. In Aim 1, we will perform CRISPR-based screens to map functional domain(s) of LSD1 responsible for its metastasis suppression vs. proliferation/survival-supporting roles, and test if LSD1 mutations found in patients impair its metastasis suppression function via disruption of the demethylase activity. In Aim 2, we will determine roles of LSD1 targets (e.g., TRIM37 and its partner EZH2, and others) of luminal cells at different steps of the metastatic cascade in various MIND models. In Aim 3, we will determine the immune mechanism mediating increased PyMT metastasis associated with LSD1 ablation, in particular, NK cells and MHC-I molecules, as LSD1-loss in PyMT tumor cells led to a profound upregulation of various classic and non-classic MHC-Is, which serve as ligands for inhibitory receptors in NK cells.

在原发肿瘤及其相应的转移性病变中发现的基因突变进行了比较