A premalignant chronology of cell-state variability in basal-like breast cancer

基底样乳腺癌细胞状态变异的癌前年表

基本信息

批准号：
10540784
负责人：
Kevin A Janes
金额：
$ 64.24万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10540784
关键词：
African American population Appearance B-Lymphocytes BRCA1 gene Breast Breast Cancer Genetics Breast conservation Carcinoma Cells Chronology Clonal Expansion Collaborations Data Disease Dissociation Duct (organ) structure Ecosystem Endowment Epithelial Cells Event Gene Expression Gene Expression Regulation Genes Genetic Genetic Predisposition to Disease Genetic Transcription Genetically Engineered Mouse Genomics Germ-Line Mutation Gland Goals Heterogeneity Human Immune Immune system In Situ In Situ Lesion Individual Intervention Knock-out Label Lesion Lymphoid Cell Macrophage Malignant Neoplasms Mammary gland Measures Mediating Methods Mitosis Molecular Mus Myeloid Cells Neoplasm Metastasis Noninfiltrating Intraductal Carcinoma Null Lymphocytes Oncogenic Organoids Phenotype Play Premalignant Cell Prevention Preventive therapy Prognosis Puberty Receptor Protein-Tyrosine Kinases Role Route Signal Transduction Somatic Mutation Statistical Data Interpretation Stress T-Lymphocyte TNF gene TP53 gene Testing Tissues Trees Tumor Suppressor Proteins Uncertainty Variant Visualization Woman Work breast stem cell breast tumorigenesis cancer cell cancer type cell type extracellular functional loss immune cell infiltrate in vivo innovation lead candidate malignant breast neoplasm mammary member mosaic mosaic analysis mutant neoplastic cell novel paracrine pharmacologic premalignant progenitor recruit success targeted treatment tool transcription factor transcriptome transcriptomics tumor tumor initiation tumor progression tumorigenesis

African American population Appearance B-Lymphocytes BRCA1 gene Breast Breast Cancer Genetics Breast conservation Carcinoma Cells Chronology Clonal Expansion Collaborations Data Disease Dissociation Duct (organ) structure Ecosystem Endowment Epithelial Cells Event Gene Expression Gene Expression Regulation Genes Genetic Genetic Predisposition to Disease Genetic Transcription Genetically Engineered Mouse Genomics Germ-Line Mutation Gland Goals Heterogeneity Human Immune Immune system In Situ In Situ Lesion Individual Intervention Knock-out Label Lesion Lymphoid Cell Macrophage Malignant Neoplasms Mammary gland Measures Mediating Methods Mitosis Molecular Mus Myeloid Cells Neoplasm Metastasis Noninfiltrating Intraductal Carcinoma Null Lymphocytes Oncogenic Organoids Phenotype Play Premalignant Cell Prevention Preventive therapy Prognosis Puberty Receptor Protein-Tyrosine Kinases Role Route Signal Transduction Somatic Mutation Statistical Data Interpretation Stress T-Lymphocyte TNF gene TP53 gene Testing Tissues Trees Tumor Suppressor Proteins Uncertainty Variant Visualization Woman Work breast stem cell breast tumorigenesis cancer cell cancer type cell type extracellular functional loss immune cell infiltrate in vivo innovation lead candidate malignant breast neoplasm mammary member mosaic mosaic analysis mutant neoplastic cell novel paracrine pharmacologic premalignant progenitor recruit success targeted treatment tool transcription factor transcriptome transcriptomics tumor tumor initiation tumor progression tumorigenesis

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项目摘要

PROJECT SUMMARY/ABSTRACT Basal-like carcinoma is a rapidly-progressing and highly variable subtype of breast cancer that arises spontaneously (often in African Americans) or in genetically predisposed women. Such tumors are believed to arise from the functional loss of the BRCA1 and TP53 tumor suppressors in uncommitted basoluminal progenitors of the breast. However, it has been challenging to dissect the origins of the disease for lack of appropriate tools, making it difficult to conceive of how the cell-state variability of premalignant mutants gives rise to basal-like breast cancer. The long-term goal of this work is to identify the critical cellular and molecular transitions underlying basal-like breast cancer genetics. The current application deploys a novel genetically engineered mouse model called mosaic analysis of double markers (MADM), which randomly deletes murine Brca1–Trp53 in transit-amplifying progenitors of the mammary gland. In MADM, stochastic deletion is genetically defined by coexpression of GFP, allowing locally expanded premalignant lesions to be visualized within the gland before the onset of basal-like disease. We found that premalignant expansion is accompanied by extensive recruitment of specific immune subsets, suggesting they play crucial roles in tumorigenesis. Our objective is to combine MADM with innovative methods for dissociation-free transcriptomics that will identify cell-state variabilities within mutant epithelial cells and the infiltrating immune lineages of a premalignancy. The hypothesis is that epithelial-cell plasticity and the stromal microenvironment coordinately diversify mutant lesions, revealing premalignant transcriptional states that ultimately progress to basal-like cancer in the breast and mammary gland. The aims of the proposal are: 1) To define shared premalignant trajectories of basoluminal diversification triggered by BRCA1–TP53 deficiency in mice and humans. 2) To deconvolve the immune heterogeneities that are locally paired with specific premalignant ecosystems for basal-like breast cancer. 3) To functionally validate cell states important for progression by using genetic, pharmacologic, and paracrine perturbations that homogenize intrinsic or extrinsic variability of premalignant cells ex vivo. Co-PIs Janes and Zong are thought leaders in their respective fields of intratumor cell-state heterogeneity and genetically engineered mouse modeling with a multi-year track record of collaboration. Together with a pair of senior clinicians, the team is poised to have a significant overall impact on our understanding of basal-like breast tumorigenesis.

项目摘要/摘要基底样癌是乳腺癌的快速促进和高度可变的亚型赞助（通常在非裔美国人）或遗传性易感性妇女。据信这样的肿瘤由BRCA1和TP53肿瘤补充剂的功能损失引起乳房的祖细胞。但是，由于缺乏适当的工具，使得难以构想的细胞态变异性如何给出成为基本的乳腺癌。这项工作的长期目标是确定关键的细胞和分子低音样乳腺癌遗传学的过渡。当前的应用程序部署了新颖的遗传学工程鼠标模型称为双标记的马赛克分析（MADM），该模型随机删除鼠 BRCA1 – TRP53在乳腺的过渡祖细胞中。在Madm中，随机删除是通常由GFP共表达定义，允许可视化局部扩展的预立衰变在低音样疾病发作之前的腺体内。我们发现预先扩展已完成通过广泛募集特定的免疫物种，表明它们在肿瘤发生中起着至关重要的作用。我们的目的是将MADM与无解离转录组学的创新方法相结合，以识别突变上皮细胞中的细胞状态变异性和预示威的浸润免疫谱系。假设是上皮细胞的可塑性和基质微环境协调多样化突变体病变，揭示了最终发展为乳腺碱性癌的前转录状态和乳腺。该提案的目的是：1）定义小鼠和人类BRCA1 -TP53缺乏触发的基底多样化。 2）脱卷免疫异质性与特定的前态生态系统局部配对，用于基本的乳房癌症。 3）通过使用遗传，药理和旁分泌扰动，使前体细胞的固有或外部变异性均质。 co 简斯（Janes）和Zong（Zong）是各自肿瘤内细胞状态异质性和具有多年协作记录的基因工程鼠标建模。一对高级临床医生，该团队被毒死，对我们对基本的理解产生重大影响乳腺肿瘤发生。