Intratumor heterogeneity in BRCA1-mutated breast cancer metastasis

BRCA1 突变乳腺癌转移的瘤内异质性

• 批准号: 10680318
• 负责人: Tatyana Lev
• 金额: $ 4.24万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-09 至 2025-05-08
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680318
• 关键词: Animals; Antibodies; BRCA1 Mutation; BRCA1 gene; Bioinformatics; Biological Assay; Brain; Breast cancer metastasis; Cancer Biology; Cause of Death; Cell Differentiation process; Cells; Cessation of life; Chromatin; Clonal Evolution; Complex; Computer Analysis; Custom; DNA; DNA Repair; DNA copy number; DNA sequencing; Data; Development; Disease; Disseminated Malignant Neoplasm; Duct (organ) structure; Educational process of instructing; Epigenetic Process; Epithelial Cells; Evolution; Faculty; Gene Expression; Gene Expression Profile; Genetic; Genetic Transcription; Genomic Instability; Genomics; Genotype; Goals; Harvest; Heterogeneity; Human Resources; Impairment; Injections; Investigation; Laboratories; Laboratory Animals; Learning; Liver; Localized Malignant Neoplasm; Lung; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mentors; Metastatic breast cancer; Methodology; Milk; Mission; Modeling; Mouse Strains; Multiomic Data; Mus; Mutant Strains Mice; Mutate; Mutation; Mutation Analysis; Myoepithelial cell; Neoplasm Metastasis; Organ; Patients; Pattern; Phenotype; Pilot Projects; Population; Positioning Attribute; Postdoctoral Fellow; Primary Neoplasm; Property; RNA; Resistance; Resolution; Students; Surveys; Systems Biology; TP53 gene; Techniques; Technology; Testing; Training; Trees; Variant; Woman; Work; XCL1 gene; advanced breast cancer; bioinformatics tool; cancer cell; cancer genomics; cell type; data integration; design; epigenomics; exome; exome sequencing; experimental study; genomic tools; improved; innovation; insight; malignant breast neoplasm; mammary epithelium; metastatic process; molecular marker; molecular oncology; molecular pathology; mouse model; multiple omics; mutant; neoplastic cell; personalized medicine; prevent; progenitor; stem cells; symposium; transcriptomics; tumor; tumor heterogeneity; undergraduate student

Abstract Metastasis continues to cause the vast majority of breast cancer related deaths because the metastatic process is poorly understood and therapies for effectively inhibiting it do not exist. Women with BRCA1 mutations develop the most aggressive, and highly metastatic basal-like breast cancer at a high rate. Despite resembling basal epithelial cells, recent studies have identified the luminal progenitor as the cell type which undergoes malignant transformation in basal-like breast cancer. Preliminary sequencing data included in this proposal, from same-cell gene expression and chromatin accessibility epigenetics assay in a mouse model of basal-like breast cancer, reveal the presence of several differentiation states of luminal progenitor cells within the tumor. Additionally, several tumor cell states appear to have unique DNA copy-number mutational signatures. These observations prompt the questions of whether a particular differentiation state is involved in metastasis and if mutations drive the differentiation and metastasis trajectory. To investigate the metastatic potentials of the cellular differentiation states and mutational cell subpopulations in the tumors, the proposed study will consist of the following methodological steps: 1) harvesting spontaneously generated Brca1&p53-mutant mouse tumors, 2) injection of tumor cells into mice to generate metastasis replicates, 3) isolation of metastatic cells using mouse strain-specific antibodies, 4) splitting of metastatic cells and original mammary tumor cells for parallel single cell profiling with a) gene expression and chromatin accessibility assay and b) custom-built high-resolution mutation panel, 5) data integration to incorporate the contribution of mutations, epigenetic chromatin states, and gene expression, 6) computational comparison of metastatic cells to original tumor cells. This study is expected to reveal the molecular markers which define metastatic cells in Brca1&p53-mutant tumors to inspire metastasis inhibiting therapy. This study will be carried out by a student with substantial training in molecular pathology and systems biology who wishes to further her cancer genomics and bioinformatics training. Laboratory animal personnel will assist with animal work, the bioinformatics director will guide the computational analysis and statistical tests, and the faculty advisor/sponsor will oversee experiments and interpretations of results. The student will work closely with the sponsor and the bioinformatics collaborator to learn the proper use of cutting edge genomics and bioinformatics tools to advance the breast cancer metastasis field. Additionally, the student will be given professional development opportunities such as attending conferences, mentoring undergraduates, and teaching a summer course to prepare her for a post-doctoral position in a cancer-related field.

抽象的 转移继续导致绝大多数乳腺癌相关的死亡，因为转移 过程知之甚少，并且可以有效抑制其不存在的疗法。患有BRCA1的女性 突变以高速率发展出最具侵略性，高度转移性的基础样乳腺癌。尽管 类似于基础上皮细胞，最近的研究已将腔祖先确定为细胞类型 在基础样乳腺癌中经历了恶性转化。其中包括的初步测序数据 提案，来自同一细胞基因表达和染色质可及性表观遗传学测定在小鼠模型中 基础样的乳腺癌，揭示了腔内祖细胞的几种分化状态 肿瘤。此外，几个肿瘤细胞态似乎具有独特的DNA拷贝数突变 签名。这些观察结果促使有关特定分化状态是否参与的问题 转移和如果突变驱动分化和转移轨迹。 研究细胞分化态和突变细胞亚群的转移电位 在肿瘤中，拟议的研究将包括以下方法论：1）收获 自发产生的BRCA1和P53突变小鼠肿瘤，2）将肿瘤细胞注射到小鼠中以产生 转移重复，3）使用小鼠应变特异性抗体分离转移细胞，4）分裂 转移细胞和原始乳腺肿瘤细胞，用于平行单细胞分析，a）基因表达和 染色质可及性测定和b）定制的高分辨率突变面板，5）数据集成到 结合突变，表观遗传染色质状态和基因表达的贡献，6）计算 转移细胞与原始肿瘤细胞的比较。这项研究有望揭示分子标记 这定义了BRCA1和p53突变肿瘤中的转移细胞，以激发转移抑制疗法。 这项研究将由对分子病理学和系统生物学进行大量培训的学生进行 希望进一步促进她的癌症基因组学和生物信息学培训。实验室动物人员将协助 通过动物工作，生物信息学总监将指导计算分析和统计测试，并指导 教师顾问/赞助商将监督结果的实验​​和解释。学生将密切工作 与赞助商和生物信息学合作者一起学习尖端基因组学和 生物信息学工具可以推进乳腺癌转移领域。此外，将向学生提供 专业发展机会，例如参加会议，指导本科生和 教夏季课程为她准备在与癌症有关的领域中的博士后职位做好准备。