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

基本信息

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
项目类别：
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

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

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项目摘要

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.

抽象的转录因子（TF）网络对于通过维持细胞身份抑制癌症发展至关重要。 TF网络是层次组织的，通过定义细胞类型，先锋TF对细胞身份至关重要特定的Cistromes。毫不奇怪，在癌症发展过程中累积的（EPI）遗传损害，包括先锋TF的放松管制，损坏TF网络功能并损害细胞身份。损坏的有转化风险的细胞会经历衰老，这是一种以A为特征的肿瘤抑制机制稳定的增殖停滞和衰老相关的分泌表型（SASP）。而衰老块受损细胞的扩散，衰老细胞可以通过细胞自主和细胞非自主机制。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伽马（TFAP2C）是指定乳腺上皮命运的先驱TF。在乳腺癌中经常观察到TFAP2C的放松管制，导致可塑性增加，并且与生存率降低。该证据表明TFAP2C放松管制有助于乳腺癌发展通过破坏细胞身份。有利于原源性基因表达和癌症发育过程中TFAP2C放松管制引起的中间衰老状态的存在，但是，仍然未知。我们以前揭示了癌基因诱导的衰老（OIS）TF网络和将TFAP2C识别为在体内稳态和OI中扮演上下文依赖角色的TF。在稳态，TFAP2C 促进细胞类型特异性转录，而在OIS TFAP2C上控制SASP基因的表达。令人惊讶的是，成纤维细胞和人类上皮乳细胞（HMEC）中TFAP2C的下调导致可塑性增加的衰老状态。基于这些集体数据，我假设对 TFAP2C通过破坏TF网络功能来破坏细胞身份，导致过渡性衰老有利于癌症的状态。为了检验此假设，我将我）生成和调节TFAP2C网络在HMEC中的OIS期间，ii）确定TFAP2C放松管制对细胞身份的功能后果，而III）识别和表征由体内TFAP2C破坏引起的衰老细胞。这项研究将提供关键对癌症进展过程中TF网络重组的见解，这是第一个体内证据衰老状态是由于先驱TF的破坏而引起的，并揭示了乳房的治疗责任患有TFAP2C放松管制的癌症。我的职业目标是成为专注于 TF网络的生物学。为此，我设计了一个严格的K22程序，其中包括专家的咨询公司在乳腺癌中，细胞重编程和基因组编辑，参加专门会议和职业开发课程和咨询委员会将监控我的进步。职业发展计划将在罗格斯新泽西医学院（NJMS）举行，该学校为通过其最先进的设施，研究和行政支持来开发年轻的研究人员。