Tumor-promoting functions of TMPRSS13 in breast cancer progression

TMPRSS13 在乳腺癌进展中的促肿瘤功能

基本信息

批准号：
10435484
负责人：
Karin List
金额：
$ 30.96万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10435484
关键词：
Agreement Apoptosis Biochemistry Biological Biological Assay Breast Cancer Cell Breast Cancer Model Breast Cancer Treatment Breast Cancer cell line Breast Cancer therapy Breast Carcinoma Breast Epithelial Cells Cancer Etiology Cancerous Cell Culture Techniques Cell Line Cell Survival Cell model Cell surface Cellular Assay Cessation of life Clinical Collaborations Collection Combined Modality Therapy Critical Pathways Data Disease Distant Drug Targeting Drug resistance Endothelium Extracellular Matrix Family Goals Growth Human Impairment Induction of Apoptosis Invaded Knowledge Liquid Chromatography Malignant - descriptor Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Mammary Tumorigenesis Maps Mass Spectrum Analysis Mediating Mesenchymal Metastatic Neoplasm to the Lung Molecular Mus N-terminal Nature Neoplasm Metastasis Non-Malignant Oncogenic Patients Peptide Hydrolases Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacotherapy Plant Resins Play Positioning Attribute Primary Neoplasm Process Proteins Proteolysis Proteome Regulation Resistance Resistance development Risk Role Serine Serine Protease Signal Pathway Signal Transduction Site Snails Testing Therapeutic Effect Tissue Sample Tissues Transcript Transcriptional Regulation Tumor Promoters Woman Work Zinc Fingers anti-cancer base breast cancer progression cancer cell chemotherapy differential expression drug discovery drug testing effective therapy efficacy evaluation epithelial to mesenchymal transition experimental study in vitro testing in vivo infiltrating duct carcinoma inhibitor innovation knock-down malignant breast neoplasm member mouse model neoplastic cell new therapeutic target novel patient derived xenograft model peptidomimetics prevent side effect slug standard of care tandem mass spectrometry three dimensional cell culture tool transcription factor transcriptome transcriptome sequencing translational applications triple-negative invasive breast carcinoma tumor tumor growth tumor initiation tumor progression

项目摘要

Abstract: TMPRSS13 is a cell-surface anchored serine protease that is up-regulated in human breast carcinoma cancer cells compared to normal breast epithelial cells. Using a TMPRSS13 deficient mouse model, we found that TMPRSS13 plays a causal role in mammary carcinogenesis, where it contributes significantly to primary tumor initiation, growth, and metastasis to the lungs. In cultured human breast cancer cells, silencing of TMPRSS13 causes decreased proliferation and increased apoptosis. The overarching goal is to validate TMPRSS13 as a potential new therapeutic target in breast cancer. We will perform both functional and mechanistic experiments to pinpoint the role of TMPRSS13 in breast cancer using parallel and complimentary hypothesis-driven experiments and unbiased approaches. The central hypothesis to be tested is that TMPRSS13 promotes tumor progression by activating pro- survival and pro-invasive signaling and represents a novel target for breast cancer treatment. We formulated three independent specific aims to test this hypothesis. In Aim 1, we will determine how TMPRSS13 promotes pro-survival and invasion. We discovered that two central regulators of epithelial-to-mesenchymal transition (EMT), and members of the Snail zinc-finger transcription factor family, Snail and Slug, are regulated by TMPRSS13. The significance of this finding and the functional relationship between TMPRSS13 and Snail/Slug will be tested in a variety of cellular assays. In parallel, state-of-the-art RNA-Seq analysis and quantitative mass spectrometry will be performed to uncover differentially expressed transcripts and proteins, respectively, to identify pathways critical for TMPRSS13-mediated functions. In Aim 2, we will develop and test new inhibitors of TMPRSS13 in breast cancer cellular models. Medicinal chemistry will be used to identify TMPRSS13 inhibitors in our collection of serine protease peptidomimetic compounds that inhibit TMPRSS13 activity. Compounds will be modified at each position to increase potency, selectivity, and stability. TMPRSS13 inhibitors will be validated in 2D and 3D cell culture models of breast cancer using quantitative proliferation/survival/apoptosis, and invasion assays to assess anticancer effects. In Aim 3, we will evaluate the efficacy of novel TMPRSS13 inhibitors in vivo using patient derived xenograft (PDX) models. Conventional chemotherapeutics often cause severe side effects and carry a significant risk of developing resistance. Preliminary data indicate that TMPRSS13 targeting leads to increased chemosensitivity in breast cancer cells. Therefore, the therapeutic effect of TMPRSS13 inhibition as mono-therapy as well as combination-therapy with standard of care chemotherapy drugs in vivo will be evaluated. The combination of state-of-the art mouse models and 2D and 3D cell culture based assays with transcriptome and proteome profiling and drug discovery encompasses an innovative and impactful strategy for studying human cancerous disease.

摘要：TMPRSS13是一种细胞表面锚定的丝氨酸蛋白酶，在人乳房中被上调癌细胞与正常乳腺上皮细胞相比。使用TMPRSS13不足的鼠标模型，我们发现TMPRSS13在乳腺癌作用中起因果作用，在此贡献它对原发性肿瘤的启动，生长和向肺的转移显着。在培养的人类乳腺癌中细胞，TMPRSS13的沉默导致增殖减少和凋亡增加。总体目标是验证TMPRSS13是乳腺癌中潜在的新治疗靶标。我们将执行两个功能以及使用平行和免费假设驱动的实验和公正的方法。要测试的中心假设是TMPRSS13通过激活促进促进肿瘤进展生存和促侵入性信号传导，代表了乳腺癌治疗的新目标。我们制定了三个独立的特定目的旨在检验这一假设。在AIM 1中，我们将确定TMPRSS13如何促进亲生和入侵。我们发现上皮到间质转变的两个中心调节剂（EMT）以及蜗牛锌指转录因子家族的成员，蜗牛和sl，由 TMPRSS13。该发现的重要性以及TMPRSS13和蜗牛/sl将在各种细胞测定中进行测试。同时，最先进的RNA-seq分析和将进行定量质谱法以发现差异表达的转录本和蛋白质，即分别确定对TMPRSS13介导的功能至关重要的途径。在AIM 2中，我们将发展和在乳腺癌细胞模型中测试TMPRSS13的新抑制剂。药物化学将用于识别在我们收集的丝氨酸蛋白酶肽型化合物中，TMPRSS13抑制剂抑制TMPRSS13 活动。化合物将在每个位置修改，以提高效力，选择性和稳定性。 TMPRSS13抑制剂将在乳腺癌的2D和3D细胞培养模型中使用定量进行验证增殖/生存/凋亡，以及评估抗癌作用的入侵测定法。在AIM 3中，我们将评估新型TMPRSS13抑制剂在体内使用患者衍生的异种移植（PDX）模型的功效。传统的化学治疗剂通常会引起严重的副作用，并具有产生抗性的重大风险。初步数据表明，TMPRSS13的靶向导致乳腺癌细胞中的化学敏感性增加。因此，TMPRSS13抑制作用作为单疗法以及与联合治疗的治疗作用将评估体内的护理化学疗法药物。最先进的鼠标模型以及基于2D和3D细胞培养的测定的结合转录组和蛋白质组分析和药物发现涵盖了创新和有影响力的策略用于研究人类癌性疾病。