Molecular mechanisms regulating LMO2+ metastasis initiating cells

调节LMO2转移起始细胞的分子机制

• 批准号: 10659840
• 负责人: Shaheen Sikandar
• 金额: $ 34.44万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-17 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659840
• 关键词: Address; Adhesions; Binding; Bioinformatics; Biological Assay; Blood Vessels; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Cause of Death; Cell Adhesion Molecules; Cells; Cessation of life; Data; Development; Disease; Distant; Endothelium; Foundations; Gene Expression; Genes; Genetic Transcription; Goals; Hematopoietic stem cells; Human; IL6 gene; In Vitro; Inflammation; Inflammatory; Interleukin-1 beta; Knowledge; LMO2 gene; Link; Measures; Mediating; Metastasis Induction; Metastatic breast cancer; Minority; Minority Groups; Mission; Modeling; Molecular; Mus; Neoplasm Metastasis; Oncogenes; Pathway interactions; Patient-Focused Outcomes; Patient-derived xenograft models of breast cancer; Patients; Phenotype; Phosphorylation; Population; Population Heterogeneity; Positioning Attribute; Process; Proteins; Public Health; Recurrence; Research; Research Personnel; STAT3 gene; Sampling; Signal Transduction; Systemic Therapy; T-Lymphocyte; TNF gene; Target Populations; Testing; Therapeutic; Therapeutic Intervention; Tube; United States National Institutes of Health; Woman; cancer cell; cytokine; design; improved outcome; in vivo; innovation; insight; knock-down; malignant breast neoplasm; mimicry; mouse model; multidisciplinary; neoplastic cell; novel; novel strategies; novel therapeutic intervention; patient derived xenograft model; polyoma middle tumor antigen; prevent; research study; response; side effect; single-cell RNA sequencing; therapeutically effective; transcription factor; tumor; tumor initiation

Metastasis remains the primary cause of death in women with breast cancer. While it is well established that tumor cells are heterogeneous and minority populations within the tumor have tumor-initiating and metastatic capabilities, the identity of metastasis initiating cells (MICs) in human breast cancer remains controversial. Until we can identify these cells and study the molecular pathways regulating them, the development of new therapeutic strategies will be hindered. The long-term goal of this proposal is to understand the intrinsic and extrinsic molecular signaling regulating MICs. Recently, using single-cell RNA sequencing data from breast cancer patient samples and sophisticated computational approaches we identified an immature population of cells in breast cancer that express hematopoietic stem cell transcriptional adaptor and the T-cell oncogene, LMO2. The objective of this proposal is to determine the molecular mechanism of LMO2 in promoting metastasis. We hypothesize that LMO2+ cells are a population of MICs in breast cancer that are activated in response to inflammation and LMO2 is a key adaptor that regulates this process. Our hypothesis is based on our preliminary results that demonstrate that Lmo2+ cells are metastatic, predict poor distant recurrence-free survival in patients, LMO2 knockdown reduces metastasis in multiple human tumor models, and LMO2 is required for STAT3 activation in response to IL6 and TNFα. The rationale underlying this proposal is that αidentifying the signaling of LMO2 in metastasis will elucidate targets in MICs that are open to therapeutic intervention. Guided by strong preliminary data, our proposal will 1. Determine whether LMO2 is required for inflammation-induced metastasis. 2. Determine the detailed molecular signaling regulated by LMO2-STAT3 axis. 3. Determine whether LMO2+ cells utilize vascular mimicry to metastasize. The proposed research is significant because it will enable the design of therapeutic strategies targeting MICs in breast cancer. Previous research studies on the identification of MICs have relied on established lineage markers. The proposed research is innovative because we are focusing on a population of LMO2+ MICs that were agnostically identified from single-cell RNA sequencing in breast cancer patient samples. The proposed research will substantially enhance our understanding of MICs and lay the foundation for novel strategies to treat metastatic breast cancer.

转移仍然是女性乳腺癌患者的主要死亡原因。虽然它已经建立得很好了 肿瘤细胞是异质性的，肿瘤内的少数群体具有肿瘤的始发和转移 关于转移起始细胞(MIC)在人类乳腺癌中的功能，目前仍存在争议。直到 我们可以鉴定这些细胞并研究调节它们的分子途径，新的 治疗策略将受到阻碍。这项建议的长期目标是理解 外在分子信号调节MICs。最近，使用来自乳房的单细胞RNA测序数据 癌症患者样本和复杂的计算方法，我们确定了一个不成熟的人群 乳腺癌中表达造血干细胞转录接头和T细胞癌基因的细胞， LMO2。本研究的目的是确定LMO2促进肿瘤转移的分子机制。 我们假设LMO2+细胞是乳腺癌中的一群MIC，它们被激活以应对 炎症和LMO2是调节这一过程的关键适配器。我们的假设是基于我们初步的 结果表明，Lmo2+细胞是转移性的，预测患者的远程无复发生存率较低， 在多种人类肿瘤模型中，LMO2基因敲除可减少转移，而STAT3需要LMO2 白细胞介素6和肿瘤坏死因子α的激活。这一提议背后的基本原理是，α识别 转移中的LMO2将阐明MICs中的靶点，这些靶点可以接受治疗干预。以Strong为指导 初步数据，我们的建议将1。确定LMO2是否是炎症诱导的转移所必需的。 2.确定LMO2-STAT3轴调控的详细分子信号转导途径。3.确定LMO2+ 细胞利用血管拟态转移。拟议的研究具有重要意义，因为它将使 乳腺癌MICs靶向治疗策略的设计。前人对身份识别的研究 的麦克风依赖于已建立的谱系标记。拟议的研究具有创新性，因为我们 聚焦于从单细胞RNA测序中不可知地鉴定出的LMO2+MIC群体 乳腺癌患者样本。建议的研究将大大加强我们对中等收入国家的认识。 并为治疗转移性乳腺癌的新策略奠定了基础。