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Targeting fibrosis to change cancer outcomes

针对纤维化改变癌症结果

基本信息

批准号：
10748730
负责人：
Joey Emery Breckenridge
金额：
$ 4.77万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
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：
2023-08-15 至 2028-08-14
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10748730
关键词：
A549 Actins Adenocarcinoma Cell Affect Aging Antineoplastic Agents Apoptosis Autoimmune Automobile Driving CD8-Positive T-Lymphocytes CDKN2A gene Cancerous Cause of Death Cells Chronic Cicatrix Collagen Connective Tissue Diseases Cyclin-Dependent Kinase Inhibitor Data Deposition Diagnosis Disease Engraftment Enzymes Epithelial Cells Etiology Extracellular Matrix Fibroblasts Fibrosis Goals Growth Growth Factor Human Hypertrophy Immunofluorescence Immunologic In Vitro Inflammation Knowledge Light Link Lung Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Modeling Molecular Monitor Morbidity - disease rate Mus Myofibroblast Neoplasms Organ Organoids Outcome Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Phenotype Play Production Publishing Pulmonary Fibrosis Reporting Research Rheumatism Risk Risk Factors Role Scleroderma Signal Transduction Skin Smooth Muscle Stains Stromal Cells Sudan Black B System Systemic Scleroderma TNF gene Technology Testing Time Transforming Growth Factor beta Translating Trichrome stain method Tumor Immunity Tumor Promotion aged airway remodeling bench to bedside beta-Galactosidase cell growth cell injury cell type cytokine gain of function high voltage electron microscopy human disease idiopathic pulmonary fibrosis in vivo innovation insight knock-down loss of function lung development member muscle hypertrophy novel novel therapeutics permissiveness receptor senescence therapeutic candidate transcriptome sequencing tumor tumor growth tumorigenesis tumorigenic validation studies

项目摘要

PROJECT SUMMARY Scleroderma (SSc) patients have more than a 300% increased risk of lung cancer, or Cancerous Scleroderma (CSc). SSc is a chronic autoimmune connective tissue disease of unknown etiology, and has the highest morbidity of all rheumatologic diseases. Moreover, aging is a key risk factor in SSc patients for pathological airway remodeling or idiopathic pulmonary fibrosis (IPF), the leading cause of death in SSc patients. Intriguingly, aging is associated with increased senescent cells, likely contributing to increased fibrosis. Published reports show that fibroblasts from IPF patients are senescent and produce a pro-tumorigenic senescence associated secretory phenotype (SASP), suggesting a potential key role for senescent myofibroblasts, the key cell type responsible for fibrosis, in driving the pathogenesis of CSc. Although it is evident that there is a tight link between fibrosis and cancer in CSc, the directionality of this progression and molecular circuits linking the two are unknown. Published data by our lab show that the TNF superfamily member 14, LIGHT, signals through LTβR expressed on myofibroblasts to drive collagen deposition and α-smooth muscle actin hypertrophy – the hallmarks of fibrosis. Our novel preliminary data suggests that senescent myofibroblasts drive cancer in a LIGHT dependent manner: In gain-of-function studies, intratracheal (I.T.) LIGHT led to enhanced fibrosis and senescent myofibroblasts in aged mice, while in loss-of-function studies comparing aged to young mice given lung adenocarcinoma cells I.T., LIGHT deletion abrogated cancer engraftment in aged mice, while young WT and LIGHT-/- mice were protected from cancer engraftment. Additionally, in a mouse lung organoid system, we showed that senescent myofibroblasts expressing LTβR increase tumor growth. Therefore, we hypothesize that senescent myofibroblasts are responsible for driving pulmonary fibrosis in scleroderma and promote lung cancer through expression of a SASP. Notably, in a novel model we established of CSc, LIGHT deletion decreased fibrosis, cancer engraftment, and senescent myofibroblasts. One key question is how LIGHT affects senescent myofibroblasts to drive cancer, therefore we will address this through the following Specific Aims: 1) To identify the molecular circuits that LIGHT uses to drive cancerous scleroderma and 2) To directly investigate the role of senescent myofibroblasts in promoting cancer ex vivo. For aim 1, we will modulate LIGHT signaling and fibrosis in mice and induce our novel model of CSc, monitoring disease. For aim 2, we will use RNA-sequencing and human lung organoids to identify the molecular pathways that drive CSc downstream of LIGHT in senescent myofibroblasts to translate findings from mouse to human. The research described in aim 1 will provide an understanding as to how LIGHT signaling drives CSc pathogenesis, while the research described in aim 2 will establish the role of senescent myofibroblasts as the key players in CSc and provide key insights on how to target these cells. Upon completion of these aims, this project has the potential to identify a novel therapeutic candidate, targeting senescent myofibroblasts to reverse CSc.

项目摘要硬皮病（SSc）患者患肺癌或癌性硬皮病的风险增加300%以上（CSc）。SSc是一种病因不明的慢性自身免疫性结缔组织病，所有风湿性疾病的发病率。此外，衰老是SSc患者病理性疾病的一个关键风险因素气道重塑或特发性肺纤维化（IPF），SSc患者死亡的主要原因。有趣的是，衰老与衰老细胞的增加有关，可能导致纤维化的增加。已发表的报告显示来自IPF患者的成纤维细胞是衰老的，并产生促肿瘤发生衰老相关的分泌表型（SASP），提示衰老肌成纤维细胞的潜在关键作用，负责纤维化，驱动CSc的发病机制。尽管很明显，在CSc中纤维化和癌症之间，这种进展的方向性和连接两者的分子电路是未知的。我们实验室发表的数据显示，TNF超家族成员14，LIGHT，通过 LTβR在肌成纤维细胞上表达，以驱动胶原沉积和α-平滑肌肌动蛋白肥大- 纤维化的标志我们的新的初步数据表明，衰老的肌成纤维细胞在一个特定的细胞中驱动癌症。光依赖性方式：在功能获得性研究中，肠内（I.T.）光导致纤维化增强，衰老的肌成纤维细胞在老年小鼠中，而在功能丧失的研究中，肺腺癌细胞I.T.，LIGHT缺失消除了老年小鼠的癌症植入，而年轻的WT 并且LIGHT-/-小鼠被保护免于癌症移植。此外，在小鼠肺类器官系统中，我们结果显示，表达LTβR的衰老肌成纤维细胞增加肿瘤生长。因此，我们假设衰老的肌成纤维细胞是导致硬皮病肺纤维化的原因，通过表达SASP促进肺癌。值得注意的是，在我们建立的CSc新模型中，缺失减少了纤维化、癌移植和衰老的肌成纤维细胞。一个关键的问题是，影响衰老的肌成纤维细胞以驱动癌症，因此我们将通过以下具体方法解决这一问题目的：1）识别LIGHT用于驱动癌性硬皮病的分子电路，2）直接研究衰老的肌成纤维细胞在离体促进癌症中的作用。对于目标1，我们将调制光信号和纤维化的小鼠，并诱导我们的新模型的CSc，监测疾病。对于目标2，我们将使用 RNA测序和人类肺类器官，以确定驱动CSc下游的分子途径，衰老肌成纤维细胞中的LIGHT将小鼠的发现转化为人类。目标1中描述的研究将提供关于LIGHT信号传导如何驱动CSc发病机制的理解，而研究描述了目的2将确定衰老肌成纤维细胞作为CSc关键参与者的作用，并提供关键见解如何瞄准这些细胞完成这些目标后，该项目有可能确定一个新的治疗候选物，靶向衰老的肌成纤维细胞以逆转CSc。