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.

项目摘要 三阴性乳腺癌（TNBC）是乳腺癌中最致命和最常见的亚型 美国。尽管基于PARP抑制和免疫疗法的有希望的新药可以延长生存 在选定的患者中，有3例中有1例死于TNBC。越来越多的证据表明人类乳腺肿瘤 港口不成熟的癌细胞，这是肿瘤性癌细胞的一个独特的子集，差异不足， 能够无限期地补充癌细胞群体，并与耐药性有很强的关系。 不幸的是，研究这些细胞的现有标记基因不是特定的，排除了理性药物 发展。我们假设对未成熟癌细胞的精确鉴定可能会带来新的 革新TNBC治疗的治疗机会。我们最近表明了 每个细胞表达的基因是细胞分化状态的强大替代物，独立于已知 标记基因。我们利用这一发现来开发细胞体，这是一个预测细胞的新框架 单细胞RNA测序（SCRNA-SEQ）数据的分化状态。我们发布的数据表明未成熟 细胞体预测的癌细胞优先表达TNBC中肿瘤性必不可少的基因。在飞行员中 数据，我们从SCRNA-SEQ数据中确定了10个假定的癌细胞种群，包括至少3个未成熟的癌细胞群体 在19个原发性乳腺肿瘤中。在这里，我们建议研究超过800名TNBC患者，以确定是否不成熟 癌细胞至少代表3个不同的人群（AIM 1）；与关键的临床协变量不同（AIM 2）；是 克隆原性并产生在计算机中预测的特定后代种群（AIM 3）。为了实现这些目标，我们 将利用新的分析方法，包括一种将SCRNA-SEQ与批量整合的反卷积方法 肿瘤转录组数据以表征大规模的细胞异质性。成功完成 拟议的项目将验证和完善我们的试点数据，以促进我们对癌细胞的理解 TNBC中的种群，尤其是未成熟的细胞。因此，我们希望这项研究促进新的机会 靶向药物的开发以改善TNBC结局。