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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：
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.

原发性肿瘤与其相应转移灶中发现的基因突变的比较迄今为止未能定义导致转移的基因突变。这提出了一个概念，即它是表观遗传机制，与癌症类型特异性致癌和/或细胞类型特异性谱系程序一起工作，这可能会推动转移进展。在乳腺癌中，表观遗传异常如何驱动转移进展在很大程度上仍然难以捉摸。更好地理解这一点可能会导致新的策略来阻止乳腺癌转移。 LSD1 (KDM1A) 是第一个被鉴定的组蛋白去甲基化酶。在人类癌症中， LSD1的基因异常主要包括缺失和突变。此类缺失/突变也在转移性乳腺癌中发现，增加了 LSD1 是乳腺癌转移的可能性抑制器。事实上，在初步研究中，我们发现管腔乳腺肿瘤细胞中 LSD1 被诱导丢失 MMTV-PyMT 小鼠模型中的 LSD1 抑制剂治疗导致肺转移急剧增加。从机制上讲，在管腔乳腺细胞中，我们发现 LSD1 与 GATA3 相互作用，GATA3 是一种关键的管腔特异性蛋白。转录因子，控制与细胞间粘附和细胞周期相关的共同程序。 LSD1 正向调节 GATA3 的表达并抑制 TRIM37 的表达，TRIM37 是 LSD1 和 LSD1 的共同靶点 GATA3，编码参与基因抑制的组蛋白 H2A 泛素连接酶。重要的是，TRIM37 可能通过抑制LSD1缺失，促进管腔乳腺癌细胞的侵袭和迁移增加一些细胞粘附基因（例如 CDH1、VCL、CTNNA1）。这种表达变化也观察到 LSD1 缺失的小鼠 PyMT 肿瘤细胞。总之，这些数据表明 LSD1 可能会抑制乳房通过调节管腔细胞中去甲基化酶活性的靶基因（例如 TRIM37）来控制癌症转移依赖方式。有趣的是，LSD1 消融的 PyMT 肿瘤细胞也表现出深刻的变化免疫相关基因，表明 LSD1 还可能通过细胞外源性抑制乳腺癌转移，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（MIND） PyMT 肿瘤细胞和人雌激素受体+乳腺癌细胞系的移植模型作为我们的研究体内系统。在目标 1 中，我们将进行基于 CRISPR 的筛选来绘制 LSD1 的功能域负责其转移抑制与增殖/生存支持作用，并测试 LSD1 是否在患者中发现的突变通过破坏去甲基化酶损害其转移抑制功能活动。在目标 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 MIND 模型中，管腔细胞处于转移级联的不同步骤。在目标 3 中，我们将确定介导与 LSD1 消融相关的 PyMT 转移增加的免疫机制，特别是， NK 细胞和 MHC-I 分子，因为 PyMT 肿瘤细胞中 LSD1 缺失导致各种经典和非经典 MHC-Is，作为 NK 细胞中抑制性受体的配体。