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

• 批准号: 10737809
• 负责人: Kevin A Janes
• 金额: $ 7.11万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 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/10737809
• 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

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.

项目概要/摘要 基底样癌是乳腺癌的一种快速进展且高度变异的亚型 自发地（通常在非裔美国人中）或有遗传倾向的女性。此类肿瘤被认为 源于未承诺的基底腔内 BRCA1 和 TP53 肿瘤抑制因子的功能丧失 乳房的祖细胞。然而，由于缺乏足够的证据，剖析这种疾病的起源一直是一项挑战。 适当的工具，使得很难想象癌前突变体的细胞状态变异性如何产生 发展为基底样乳腺癌。这项工作的长期目标是确定关键的细胞和分子 基础样乳腺癌遗传学的转变。当前的应用部署了一种新颖的基因 称为双标记镶嵌分析 (MADM) 的工程小鼠模型，可随机删除小鼠 乳腺转运放大祖细胞中的 Brca1–Trp53。在MADM中，随机删除是 通过 GFP 共表达进行基因定义，使局部扩大的癌前病变可视化 基底样疾病发作之前腺体内。我们发现癌前扩张伴随着 通过广泛招募特定的免疫亚群，表明它们在肿瘤发生中发挥着至关重要的作用。我们的 目标是将 MADM 与无解离转录组学的创新方法相结合，从而识别 突变上皮细胞内的细胞状态变异性和癌前病变的浸润性免疫谱系。 假设是上皮细胞可塑性和基质微环境协调地使突变体多样化 病变，揭示癌前转录状态，最终进展为乳腺癌样基底细胞癌 和乳腺。该提案的目的是： 1) 定义共同的癌前轨迹 小鼠和人类中 BRCA1-TP53 缺陷引发的基底腔多样化。 2）去卷积 免疫异质性与基底样乳腺的特定癌前生态系统局部配对 癌症。 3) 通过使用遗传、药理学和方法来功能验证对进展重要的细胞状态 旁分泌扰动使离体癌前细胞的内在或外在变异均质化。联合PI Janes 和 Zong 是各自肿瘤内细胞状态异质性领域的思想领袖 基因工程小鼠模型具有多年的合作记录。连同一对 高级临床医生，该团队准备对我们对 basal-like 的理解产生重大的整体影响 乳腺肿瘤发生。