ATR: targeting mechanical stress induced EMT and immune suppression in triple negative breast cancer

ATR：针对三阴性乳腺癌中机械应力诱导的 EMT 和免疫抑制

• 批准号: 10658429
• 负责人: Zhenkun Lou
• 金额: $ 36.92万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658429
• 关键词: ATR gene; Behavior; Biopsy Specimen; Breast Cancer cell line; Cell Cycle; Cell Wall; Cells; Cessation of life; Clinical Trials; Complex; Cytoskeleton; DNA Damage; DNA Repair; DNA replication fork; Data; Death Rate; Deposition; Deubiquitinating Enzyme; Deubiquitination; Disease; Disease Progression; Distant Metastasis; Enrollment; Epithelial Cells; Extracellular Matrix; Genetically Engineered Mouse; Genome Stability; Goals; Health; Immune Evasion; Immune System Diseases; Immune system; Immunologic Surveillance; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Institution; Invaded; Malignant Neoplasms; Mechanical Stress; Mediating; Mesenchymal; Modeling; Neoplasm Metastasis; Nuclear; Nuclear Translocation; Pathway interactions; Patients; Phenotype; Play; Process; Prognosis; Progression-Free Survivals; Property; Proteins; Regulation; Resistance; Role; Sampling; Signal Pathway; Societies; Stimulus; Testing; Therapeutic; Tissues; Tumor Cell Invasion; Tumor Immunity; Tumor Suppressor Proteins; United States; Variant; Xenograft procedure; aggressive breast cancer; anti-PD-1; anti-PD1 therapy; ataxia telangiectasia mutated protein; beta catenin; breast cancer diagnosis; breast cancer progression; cancer cell; disorder subtype; epithelial to mesenchymal transition; fighting; in vivo; inhibitor; insight; malignant breast neoplasm; mechanical stimulus; novel strategies; peripheral blood; programs; protein expression; response; response biomarker; stem-like cell; therapy resistant; triple-negative invasive breast carcinoma; tumor; tumor progression; ubiquitin isopeptidase

PROJECT DESCRIPTION/ABSTRACT Therapeutically resistant triple negative breast cancer (TNBC) is characterized by mesenchymal features that facilitate immune evasion and disease progression, resulting in high rates of death from the disease. New strategies targeting the mesenchymal phenotype to overcome therapeutic resistance are needed. Interactions between the cytoskeleton of cancer cells and the surrounding extracellular matrix play important roles in initiating local invasion and metastasis. The resulting mechanical stimuli activate signaling pathways which promote the transition of non-motile polarized epithelial cells to cells with mesenchymal properties that are able to invade surrounding tissues and evade immune surveillance, a process termed epithelial to mesenchymal transition (EMT). Fibrotic stiffening of the non-cellular stroma resulting from extracellular matrix deposition is a common feature of TNBC and other malignancies that is associated with therapeutic resistance and poor prognosis. How mechanical stress promotes EMT and cancer progression has not been elucidated. Ataxia Telangiectasia Mutated and Rad-3 Related (ATR) is best known as a regulator of the DNA damage response in replicating cells. In our preliminary data, we have found that high ATR protein expression is associated with reduced progression-free survival in TNBC. We discovered that ATR is post-translationally upregulated by a deubiquitinating enzyme, USP21, in response to mechanical stress, and that ATR regulates the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex to promote β-catenin nuclear translocation and mechanical stress-induced EMT. This new role for ATR in mechanical stress and EMT is independent of ATR’s established function in regulating the DNA damage response. In a clinical trial of anti-PD-1 immunotherapy for advanced TNBC, high ATR levels in biopsy specimens was correlated with EMT and reduced responsiveness. ATR inhibition could promote mesenchymal to epithelial transition and anti-tumor immunity in vivo. We hypothesize that ATR regulates the LINC complex following mechanical stress to promote β-catenin mediated EMT, immune evasion, and TNBC progression. We will test this hypothesis through three specific aims. Aim 1 will examine the impact of mechanical stress on ATR deubiquitination and the LINC complex; Aim 2 will evaluate how ATR influences β-catenin pathway activation and EMT; Aim 3 will investigate the role of ATR-SUN2 in stiffness and EMT associated immune evasion.

项目描述/摘要 治疗性抗性三重阴性乳腺癌（TNBC）的特征是间充质特征 促进免疫进化和疾病进展，导致疾病的死亡率很高。新的 需要针对间充质表型克服治疗抗性的策略。互动 在癌细胞的细胞骨架和周围的细胞外基质之间起着重要作用 局部入侵和转移。由此产生的机械刺激激活信号通路，以促进 非运动偏振上皮细胞向具有间质特性的细胞过渡，能够入侵 周围组织和逃避免疫监视，这一过程称为间质转变 （EMT）。由细胞外基质沉积引起的非细胞基质的纤维化僵硬是常见的 TNBC和其他与治疗性抗性和预后不良有关的恶性肿瘤的特征。如何 机械应力会促进EMT，并且尚未阐明癌症进展。 共济失调的毛细血管扩张突变和RAD-3相关（ATR）是DNA损伤的调节剂 复制细胞的响应。在我们的初步数据中，我们发现高ATR蛋白表达是 与TNBC中无进展生存的降低有关。我们发现ATR是后翻译的 通过除泛素化酶USP21的更新，以响应机械应力，并且ATR调节 核骨骼和细胞骨架（LINC）复合物的接头，以促进β-catenin核易位和 机械应力诱导的EMT。 ATR在机械压力和EMT中的新角色与ATR无关 在调节DNA损伤反应方面已建立的功能。在抗PD-1免疫疗法的临床试验中 晚期TNBC，活检标本中的高ATR水平与EMT相关并降低了响应能力。 ATR抑制作用可以促进对体内上皮过渡和抗肿瘤免疫的间质。我们 假设ATR在机械应力下调节LINC络合物以促进β-catenin介导 EMT，免疫驱逐和TNBC进展。我们将通过三个特定目标检验这一假设。目标1 将检查机械应力对ATR去泛素化和林族复合物的影响； AIM 2将评估 ATR如何影响β-catenin途径激活和EMT； AIM 3将调查ATR-SUN2在 刚度和EMT相关的免疫进化。