Loss of Cell Identity as a Prerequisite for Breast Cancer Development

细胞身份的丧失是乳腺癌发生的先决条件

• 批准号: 10350349
• 负责人: Ricardo Ivan Martinez Zamudio
• 金额: $ 19.47万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-07 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10350349
• 关键词: ATAC-seq; Advisory Committees; Animal Model; Area; Binding; Biology; Breast Cancer Cell; Breast Epithelial Cells; Bypass; Cell Aging; Cell Maintenance; Cells; ChIP-seq; Chromatin; Coculture Techniques; Data; Data Set; Dedications; Development; Development Plans; Down-Regulation; ERBB2 gene; Endowment; Enhancers; Environment; Epithelial Cells; Epithelium; Fibroblasts; Gene Expression; Genes; Genetic; Genetic Transcription; Genomics; Goals; Growth; Histones; Homeostasis; Human; Immunofluorescence Immunologic; Immunohistochemistry; Knockout Mice; Knowledge; Lead; MCF10A cells; Malignant - descriptor; Malignant Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Methods; Molecular; Monitor; Mus; New Jersey; Oncogenes; Oncogenic; Patients; Phenotype; Play; Proliferating; Regulatory Element; Research; Research Personnel; Risk; Role; Specific qualifier value; Stress; TFAP2C gene; Testing; The Cancer Genome Atlas; Therapeutic; Time; Tissues; Transcription Factor AP-2 Gamma; Transcriptional Regulation; Tumor Suppressor Proteins; Up-Regulation; cancer cell; cancer therapy; career; career development; cell injury; cell type; conditional knockout; course development; design; epigenome; epigenomics; epithelial to mesenchymal transition; experimental study; extracellular; genome editing; in vivo; induced pluripotent stem cell; insight; malignant breast neoplasm; mammary; medical schools; overexpression; paracrine; programs; senescence; stem cells; stemness; symposium; therapy resistant; transcription factor; transcriptome sequencing; tumor progression

ABSTRACT Transcription Factor (TF) networks are critical in suppressing cancer development by maintaining cell identity. TF networks are hierarchically organized, with pioneer TFs being critical to cell identity by defining cell type- specific cistromes. Not surprisingly, the (epi)genetic damage that accumulates during cancer development, including deregulation of pioneer TFs, corrupts TF network function and compromises cell identity. Damaged cells at risk of transformation can undergo senescence, a tumor suppressor mechanism characterized by a stable proliferative arrest and a senescence-associated secretory phenotype (SASP). While senescence blocks proliferation of damaged cells, senescent cells can facilitate cancer development through cell autonomous and cell non-autonomous mechanisms. As such, senescent cells are an attractive target for anti-cancer therapies. Transcription Factor AP-2 gamma (TFAP2C) is a pioneer TF that specifies the mammary luminal epithelial fate. Deregulation of TFAP2C is frequently observed in breast cancer, leads to increased plasticity, and is associated with reduced survival. This evidence suggests that TFAP2C deregulation facilitates breast cancer development by disrupting cell identity. The epigenomic reorganization required to favor protumorigenic gene expression and the existence of intermediate senescence states arising from TFAP2C deregulation during cancer development, however, remain unknown. We previously revealed the oncogene-induced senescence (OIS) TF network and identified TFAP2C as a TF that plays context-dependent roles in homeostasis and OIS. In homeostasis, TFAP2C facilitates cell type-specific transcription, while upon OIS TFAP2C controls the expression of SASP genes. Surprisingly, downregulation of TFAP2C in fibroblasts and human epithelial mammary cells (HMECs) leads to a senescence state with increased plasticity. Based on these collective data, I hypothesize that deregulation of TFAP2C disrupts cell identity by corrupting TF network function, leading to a transitional senescent state that is conducive to cancer. To test this hypothesis, I will i) generate and modulate TFAP2C networks during OIS in HMECs, ii) identify the functional consequences of TFAP2C deregulation on cell identity, and iii) identify and characterize senescent cells arising from TFAP2C disruption in vivo. This study will provide critical insights into the reorganization of TF networks during cancer progression, the first in vivo evidence of a senescence state arising from disruption of a pioneer TF and reveal therapeutically exploitable liabilities in breast cancers with TFAP2C deregulation. My career goal is to become an independent investigator focusing on the biology of TF networks. To this end, I designed a rigorous K22 program that includes the consultancies of experts in breast cancer, cellular reprogramming and genome editing, attendance to dedicated conferences and career development courses, and an Advisory Committee that will monitor my progress. The career development plan will take place at Rutgers New Jersey Medical School (NJMS), which provides an excellent environment for the development of young investigators through its state-of-the-art facilities, research and administrative support.

摘要 转录因子（TF）网络在通过维持细胞身份来抑制癌症发展方面至关重要。 TF网络是分层组织的，先锋TF通过定义细胞类型对细胞身份至关重要- 具体的cistromes。毫不奇怪，在癌症发展过程中积累的（epi）遗传损伤， 包括解除对先驱TF的管制，破坏TF网络功能并损害小区身份。损坏 处于转化风险的细胞可以经历衰老，这是一种肿瘤抑制机制，其特征在于： 稳定增殖停滞和衰老相关分泌表型（SASP）。当衰老阻碍 衰老细胞可以通过细胞自主和细胞增殖促进癌症的发展， 细胞非自主机制。因此，衰老细胞是抗癌疗法的有吸引力的靶标。 转录因子AP-2 γ（TFAP 2C）是指定乳腺腔上皮命运的先驱TF。 在乳腺癌中经常观察到TFAP 2C的失调，导致可塑性增加，并且与乳腺癌的发生有关。 生存率降低。这一证据表明，TFAP 2C失调促进乳腺癌的发展 通过破坏细胞的身份表观基因组重组有利于促肿瘤基因表达， 在癌症发展过程中存在由TFAP 2C失调引起的中间衰老状态， 但仍不清楚。我们先前揭示了癌基因诱导衰老（OIS）TF网络， 将TFAP 2C鉴定为在稳态和OIS中起情境依赖性作用的TF。在稳态中，TFAP 2C 促进细胞类型特异性转录，而在OIS时，TFAP 2C控制SASP基因的表达。 令人惊讶的是，TFAP 2C在成纤维细胞和人乳腺上皮细胞（HMEC）中的下调导致 可塑性增强的衰老状态。根据这些数据，我假设放松管制 TFAP 2C通过破坏TF网络功能破坏细胞身份，导致过渡性衰老 这是一个容易导致癌症的状态。为了验证这一假设，我将i）生成并调节TFAP 2C网络 在HMEC中的OIS期间，ii）鉴定TFAP 2C失调对细胞身份的功能后果，和iii） 鉴定和表征由体内TFAP 2C破坏产生衰老细胞。这项研究将提供关键的 深入了解癌症进展期间TF网络的重组，这是第一个体内证据， 衰老状态由先驱TF的破坏引起，并揭示了乳腺癌中治疗上可利用的责任 TFAP 2C失调的癌症。我的职业目标是成为一名独立调查员， TF网络的生物学为此，我设计了一个严格的K22计划，其中包括专家咨询 在乳腺癌、细胞重编程和基因组编辑方面，参加专门会议和职业生涯 发展课程，和一个咨询委员会，将监测我的进展。职业发展计划 将在罗格斯新泽西医学院（NJMS）举行，这为学生提供了一个良好的环境。 通过其最先进的设施、研究和行政支持，培养年轻的调查人员。