Delineating developmental programs driving tumorigenesis in triple-negative breast cancer

描绘驱动三阴性乳腺癌肿瘤发生的发育程序

• 批准号: 10558695
• 负责人: Aaron M Newman
• 金额: $ 50.54万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558695
• 关键词: 3-Dimensional; Address; Affect; African American; Automobile Driving; Bioinformatics; Biological Assay; Breast; Breast Cancer Patient; Breast Cancer Treatment; Cancer Detection; Cells; Clinical; Data; Data Set; Development; Disease; Drug Targeting; Drug resistance; Foundations; Gene Expression Profile; Genes; Growth; Heterogeneity; Human; Immunotherapy; Knowledge; Link; Malignant Neoplasms; Mammary Neoplasms; Methods; Modeling; Molecular; Normal tissue morphology; Organoids; Outcome; PARP inhibition; Patient Selection; Patients; Population; Publishing; Race; Science; Specimen; Surface; Surgical Oncology; Treatment Failure; Tumorigenicity; United States; Validation; analytical method; analytical tool; cancer cell; cancer subtypes; chemotherapy; cohort; cytotoxic; drug development; effective therapy; exome sequencing; human tissue; improved; in silico; innovation; malignant breast neoplasm; mortality; mutant; new therapeutic target; novel therapeutics; programmed cell death ligand 1; programs; relapse patients; single-cell RNA sequencing; stem cell biology; therapy resistant; transcriptome; transcriptomics; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor heterogeneity; tumorigenesis; tumorigenic

PROJECT SUMMARY Triple-negative breast cancer (TNBC) is the deadliest and 2nd most common subtype of breast cancer in the United States. Although promising new drugs based on PARP inhibition and immunotherapy can extend survival in selected patients, 1 in 3 patients die from TNBC. Increasing evidence suggests that human breast tumors harbor immature cancer cells which are a distinct subset of tumorigenic cancer cells, are less-differentiated, capable of replenishing cancer cell populations indefinitely, and strongly implicated in drug resistance. Unfortunately, existing marker genes for studying these cells are not specific, precluding rational drug development. We hypothesize that precise identification of immature cancer cells could present new therapeutic opportunities to revolutionize TNBC treatment. We recently showed that the number of expressed genes per cell is a powerful surrogate of cellular differentiation status independently of known marker genes. We leveraged this finding to develop CytoTRACE, a new framework for predicting cellular differentiation status from single-cell RNA sequencing (scRNA-seq) data. Our published data show that immature cancer cells predicted by CytoTRACE preferentially express genes essential for tumorigenicity in TNBC. In pilot data, we identified 10 putative cancer cell populations, including at least 3 immature ones, from scRNA-seq data of 19 primary breast tumors. Here, we propose to study over 800 TNBC patients to determine whether immature cancer cells represent at least 3 distinct populations (Aim 1); differ by key clinical covariates (Aim 2); and are clonogenic and produce specific progeny populations predicted in silico (Aim 3). To accomplish these aims, we will leverage new analytical methods, including a deconvolution approach for integrating scRNA-seq with bulk tumor transcriptomic data in order to characterize cellular heterogeneity at scale. Successful completion of the proposed project will validate and refine our pilot data toward advancing our understanding of cancer cell populations, especially immature cells, in TNBC. As such, we expect this study to facilitate new opportunities for the development of targeted drugs to improve TNBC outcomes.

项目概要 三阴性乳腺癌 (TNBC) 是世界上最致命且第二常见的乳腺癌亚型 美国。尽管基于 PARP 抑制和免疫疗法的有前途的新药可以延长生存期 在选定的患者中，三分之一的患者死于 TNBC。越来越多的证据表明人类乳腺肿瘤 含有未成熟的癌细胞，它们是致瘤癌细胞的一个独特子集，分化程度较低， 能够无限地补充癌细胞群，并且与耐药性密切相关。 不幸的是，用于研究这些细胞的现有标记基因并不具有特异性，从而排除了合理的药物 发展。我们假设，对未成熟癌细胞的精确识别可能会带来新的结果。 彻底改变 TNBC 治疗的治疗机会。我们最近表明，数量 每个细胞表达的基因是独立于已知的细胞分化状态的有力替代品 标记基因。我们利用这一发现开发了 CytoTRACE，一种用于预测细胞的新框架 单细胞 RNA 测序 (scRNA-seq) 数据的分化状态。我们公布的数据表明，不成熟 CytoTRACE 预测的癌细胞优先表达 TNBC 中致瘤性所必需的基因。试点中 数据中，我们从 scRNA-seq 数据中识别出 10 个假定的癌细胞群，包括至少 3 个未成熟细胞群 19 个原发性乳腺肿瘤。在这里，我们建议对 800 多名 TNBC 患者进行研究，以确定是否不成熟 癌细胞代表至少 3 个不同的群体（目标 1）；因关键临床协变量而异（目标 2）；并且是 克隆形成并产生计算机预测的特定后代群体（目标 3）。为了实现这些目标，我们 将利用新的分析方法，包括将 scRNA-seq 与批量集成的反卷积方法 肿瘤转录组数据，以大规模表征细胞异质性。圆满完成了 拟议的项目将验证和完善我们的试点数据，以增进我们对癌细胞的理解 TNBC 中的群体，尤其是未成熟细胞。因此，我们希望这项研究能够为以下领域提供新的机会： 开发靶向药物以改善 TNBC 结局。