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：
10308092
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/10308092
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 Histone H3 Human Immune Immune response Impairment Injections KDM1A gene KLRD1 gene Knowledge Lead Ligands Lysine Malignant Neoplasms Mammary Neoplasms Maps Mediating Mediator of activation protein Metastasis Suppression Metastatic Neoplasm to the Lung Metastatic breast cancer Metastatic to 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 Qa-1 Antigen Regulation Repression Role Scientist Specificity System Testing The Cancer Genome Atlas Translating Up-Regulation Work base cancer genetics 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 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.

在原发性肿瘤及其相应转移性病变中发现的遗传突变的比较具有到目前为止，未能定义导致转移的基因突变。这提出了一个表观遗传学的观念机制，与癌症类型特异性的致癌和/或细胞类型特异性谱系程序一起工作，这可能会推动转移性进展。在乳腺癌中，表观遗传异常如何驱动转移性进步基本上仍然难以捉摸。对此有更好的理解可能会导致新颖的策略阻止乳腺癌转移。 LSD1（KDM1A）是第一个鉴定出的组蛋白脱甲基酶。在人类癌症中 LSD1的遗传异常主要包括缺失和突变。这样的删除/突变也有在转移性乳腺癌中发现，提出了LSD1是乳腺癌转移的可能性抑制器。实际上，在初步研究中，我们发现腔乳腺肿瘤细胞中诱导的LSD1损失 MMTV-PYMT小鼠模型中的LSD1抑制剂处理导致肺转移的急剧增加。从机械上讲，在腔内乳房细胞中，我们发现LSD1与GATA3相互作用，GATA3是一个关键的腔特异性转录因子，以控制其与细胞 - 细胞粘附和细胞周期有关的常见程序。 LSD1 积极调节GATA3的表达并抑制Trim37，这是LSD1和 GATA3编码与基因抑制有关的组蛋白H2A泛素连接酶。重要的是，Trim37 5月通过抑制LSD1损伤的腔内乳腺癌细胞的侵袭和迁移几个细胞粘附基因（例如CDH1，VCL，CTNNA1）。在鼠PYMT肿瘤细胞具有LSD1-als。这些数据一起表明LSD1可能会抑制乳房通过调节其靶基因（例如，TRIM37）在脱甲基酶活性中的腔细胞中的癌症转移 - 依赖方式。有趣的是，具有LSD1消融的PYMT肿瘤细胞在免疫相关的基因，表明LSD1也可能抑制细胞超支的乳腺癌转移，免疫相关机制。为了测试这些，我们将继续建立小鼠导管内注射（思维） PYMT肿瘤细胞和人雌激素受体+乳腺癌细胞系的移植模型与我们体内系统。在AIM 1中，我们将执行基于CRISPR的屏幕以绘制LSD1的功能域负责其转移抑制与增殖/生存支撑角色，并测试LSD1 在患者中发现的突变通过破坏脱甲基酶损害其转移抑制功能活动。在AIM 2中，我们将确定LSD1目标（例如Trim37及其合作伙伴EZH2等）的作用在各种思维模型中，在转移级联的不同步骤处的腔细胞。在AIM 3中，我们将确定介导的免疫机制增加了与LSD1消融相关的PYMT转移，特别是 NK细胞和MHC-I分子，作为PYMT肿瘤细胞中的LSD1-alss，导致了各种深刻的上调经典和非经典MHC-IS，它们是NK细胞中抑制受体的配体。