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: 10598886
• 负责人: Kevin A Janes
• 金额: $ 3.49万
• 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/10598886
• 关键词: African American population; BRCA1 gene; Breast; Carcinoma; Cells; Chronology; Clinical; Collaborations; Communication; Complement; Critical Thinking; Disease; Ecosystem; Funding; Gene Expression; Genetic; Genetic Predisposition to Disease; Genetically Engineered Mouse; Gland; Heterogeneity; Human; Immune; Intervention; Lead; Leadership; Lesion; Malignant - descriptor; Malignant Neoplasms; Mammary gland; Mosaicism; Mus; Parents; Pharmacology; Phenotype; Premalignant Cell; Prevention strategy; Prognosis; Research Personnel; TP53 gene; Testing; Training; Tumor Suppressor Proteins; Uncertainty; Woman; base; breast tumorigenesis; cancer type; experience; experimental study; functional loss; hormonal signals; malignant breast neoplasm; mouse model; mutant; novel; paracrine; parent grant; premalignant; progenitor; skills; targeted treatment; tool; transcriptomics; treatment strategy; tumor; tumor progression

In the funded parent grant 1R01 CA256199-01A1 entitled “premalignant chronology of cell-state variability in basal-like breast cancer”, we proposed to comprehensively and progressively analyze gene expression profiles of mutant cells during the premalignant stage of basal-like breast cancer to understand how cell state plasticity could lead to tumor progression. 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 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. The aims of the parent R01 are to use transcriptomic analysis: 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. The project proposed by the supplement candidate is distinct from but perfectly complements with the experiments proposed in the parent R01: while the parent R01 focuses on delineating cell state plasticity based on gene expression profiles, her project approaches the problem from phenotype-guided functional interventions. In Specific Aim 1, she plans to investigate the involvement of aberrant hormonal signaling during premalignant progression and test potential treatment strategies. In Specific Aim 2, she will investigate whether premalignant hyperproliferation can be exploited using PARPi treatment. As a whole, these complementary experiments should not only allow us to dive more deeply into key mechanisms of premalignant progression of basal-like breast cancer, but also provide excellent training experience for the supplement candidate, including bench skills, critical thinking, scientific communication, networking with both basic and clinical researchers, and leadership skills.

在资助的母基金1 R 01 CA 256199 - 01 A1中，题为“癌前细胞状态变异性的时间表”， 基底细胞样乳腺癌”，我们建议全面和逐步分析基因表达谱 突变细胞在基底细胞样乳腺癌的癌前阶段，以了解细胞状态可塑性 可能导致肿瘤进展基底细胞样癌是一种进展迅速且高度变异的基底细胞癌亚型， 自发性乳腺癌（通常发生在非裔美国人中）或遗传易感妇女。 这种肿瘤被认为是由BRCA 1和TP 53肿瘤抑制因子的功能丧失引起的， 乳腺的未定型基底管腔祖细胞。然而，要剖析 由于缺乏适当的工具，很难想象细胞状态的变异性是如何发生的。 癌前突变体引起基底样乳腺癌。目前的应用程序部署了一种新的基因 工程小鼠模型称为双标记镶嵌分析（MADM），随机删除小鼠 Brca 1-Trp 53在乳腺的过渡扩增祖细胞。在MADM中，随机删除是 通过GFP的共表达进行遗传学定义，允许局部扩大的癌前病变被可视化 在基底细胞样疾病发作之前，亲本R 01的目的是使用转录组学 分析：1）定义BRCA 1 - 1触发的基底管腔多样化的共同癌前轨迹。 TP 53在小鼠和人类中的缺陷。2)为了反卷积局部配对的免疫异质性， 基底细胞样乳腺癌的特定癌前生态系统。3)功能验证细胞状态重要 通过使用遗传、药理学和旁分泌干扰，使内源性或 离体癌前细胞的外在变异性。联合PI Janes和Zong是各自领域的思想领袖。 肿瘤内细胞状态异质性和基因工程小鼠建模领域， 合作的记录。再加上一对高级临床医生，该团队准备有一个重大的整体 影响我们对基底细胞样乳腺肿瘤发生的理解。补充建议的项目 候选者不同于但完全补充了在父R 01中提出的实验：而 她的项目R 01的重点是根据基因表达谱描绘细胞状态的可塑性， 从表型指导的功能干预来解决问题。在具体目标1中，她计划 研究癌前进展期间异常激素信号的参与， 治疗策略。在《特定目标2》中，她将研究癌前过度增殖是否可以被 利用PARPi治疗。作为一个整体，这些互补的实验不仅可以让我们 更深入地研究基底细胞样乳腺癌癌前病变进展的关键机制， 为补充候选人提供优秀的培训经验，包括板凳技能，批判性思维， 科学沟通，与基础和临床研究人员的网络，以及领导技能。