Matricellular proteins of the CNN family as regulators of tumor-induced cachexia

CNN 家族的基质细胞蛋白作为肿瘤引起的恶病质的调节剂

基本信息

批准号：
10586444
负责人：
Sarah M Judge
金额：
$ 39.32万
依托单位：
UNIVERSITY OF FLORIDA
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 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586444
关键词：
Adipocytes Adipose tissue Antibodies Atrophic Attenuated Automobile Driving Cachexia Cancer Patient Cell Differentiation process Cell Nucleus Cell secretion Cells Communication Data Development Disease Dose EGFR inhibition Engraftment Epidermal Growth Factor Receptor Event Family Fatty acid glycerol esters Fibrosis Frequencies Functional disorder Genes Genetic Growth Factor Inhibition HIF1A gene High Prevalence Hormonal Human Hypoxia Impairment In Vitro Inflammation Injury Interleukin-6 KPC model Knock-out Knockout Mice Link MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of pancreas Measures Mediating Mediator Metabolic Molecular Mus Muscle Muscle Cells Muscle Fibers Muscle Weakness Muscular Atrophy Myopathy NF-kappa B Nature Neoplasm Metastasis Nutritional Support Operative Surgical Procedures Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Peripheral Phenotype Physical Function Play Process Production Proteins Quality of life Recombinants Role Serum Signal Transduction Skeletal Muscle Smooth Muscle Myocytes Syndrome Testing Time Tissues Up-Regulation Work autocrine cancer cachexia cancer therapy cancer type cell type connective tissue growth factor conventional therapy cytokine effective therapy energy balance fat wasting gene repression in vivo in vivo Model mouse model muscle form muscle regeneration neoplastic cell overexpression pancreatic cancer cells pancreatic cancer model pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model pancreatic neoplasm pharmacologic preservation progenitor receptor repaired respiratory response single nucleus RNA-sequencing skeletal muscle wasting small hairpin RNA transcriptome sequencing translational potential tumor tumor growth unpublished works vector

项目摘要

Summary/Abstract Cancer-associated cachexia is a multifactorial syndrome characterized by the involuntary loss of body and skeletal muscle mass (with or without fat loss) that reduces tolerance to cancer treatments, increases complications following surgery and is strongly predictive of reduced survival. However, there are currently no effective therapies to preserve, or reverse the loss of, muscle mass in cancer patients, highlighting a major gap in treatment. Unpublished work from our lab implicates a key role for Cellular Communication Network Factor 2 (CCN2), also known as connective tissue growth factor (CTGF), in mediating cachexia induced by pancreatic ductal adenocarcinoma (PDAC), a cancer type with high prevalence of cachexia. CTGF is a hypoxia-inducible matricellular protein produced by pancreatic cancer cells and PDAC tumors which functions locally to induce stromal remodeling, tumor growth and metastasis. In a mouse models of PDAC, we found that Ctgf and Hif1a are upregulated in tumors at time points corresponding to cachexia initiation and progression, suggesting CTGF production by hypoxic PDAC tumors could also be involved in cachexia. In preliminary studies we found that genetic or pharmacological targeting of CTGF inhibited cachexia and blocked host- and tumor cell-secretion of key circulating mediators of cachexia, despite controlling for CTGF-dependent effects on tumor growth, leading us to hypothesize that CTGF promotes PDAC cachexia, at least in part, through promoting cytokine-dependent signaling in peripheral tissues, which will be investigated in Aim 1. In addition to CTGF production within PDAC tumors, CTGF is also upregulated in skeletal muscles of cachectic patients and mice with PDAC. We therefore hypothesize that local production of CTGF within muscle tissue may also play a direct role in muscle wasting in response to PDAC, which was supported through targeting of Ctgf-shRNA to muscle tissue using AAV. Through single nucleus RNAseq we further identified Ctgf to be upregulated in both respiratory and peripheral skeletal muscles of PDAC mice in a cell type-specific manner, with Ctgf commonly upregulated within a subpopulation of mature skeletal muscle nuclei that show increased expression of atrophy-related genes. Using both in vitro and in vivo models, Aim 2 will thus further investigate the cell-autonomous role of Ctgf in mediating skeletal muscle wasting and dysfunction in response to PDAC, and the mechanisms involved. We anticipate that our findings will elucidate key tissue-specific mechanisms of muscle wasting and weakness associated with cancer, with high translational potential.

摘要/摘要与癌症相关的恶病质是一种多因素综合征，其特征是身体的非自愿丧失和骨骼肌质量（有或没有脂肪流失），可降低对癌症治疗的耐受性，增加手术后的并发症，并强烈预测生存率降低。但是，目前没有有效保存或扭转癌症患者肌肉质量损失的疗法，突出了一个主要差距在治疗中。我们实验室未发表的工作暗示了蜂窝通信网络因子2的关键作用2 （CCN2），也称为结缔组织生长因子（CTGF），在介导胰腺诱导的恶病质中导管腺癌（PDAC），一种癌症类型，患病率很高。 CTGF是低氧诱导的由胰腺癌细胞和PDAC肿瘤产生的母细胞蛋白，在局部发挥作用可诱导基质重塑，肿瘤生长和转移。在PDAC的鼠标模型中，我们发现CTGF和HIF1A 在肿瘤中的时间点上调，对应于恶病质开始和进展，表明CTGF 低氧PDAC肿瘤的产生也可能参与恶病质。在初步研究中，我们发现 CTGF的遗传学或药理靶向抑制恶病质，并阻塞宿主和肿瘤细胞分泌尽管控制了CTGF依赖对肿瘤生长的影响，但卡赫西亚的关键循环介质仍在我们假设CTGF至少部分通过促进细胞因子依赖性来促进PDAC Cachexia 外周组织中的信号传导，除了PDAC内的CTGF产生外，还将在AIM 1中进行研究肿瘤，CTGF在缓存患者和PDAC小鼠的骨骼肌中也被上调。因此，我们假设肌肉组织中CTGF的局部产生也可能在肌肉浪费中发挥直接作用对PDAC的反应，PDAC通过使用AAV靶向CTGF-shRNA对肌肉组织的支持。通过单核RNASEQ我们进一步确定CTGF在呼吸道和外周骨骼中被上调 PDAC小鼠的肌肉以细胞类型特异性方式，CTGF通常在亚群中上调成熟的骨骼肌核的表现出增加的与萎缩相关基因的表达增加。在体外都使用在体内模型中，AIM 2将进一步研究CTGF在介导骨骼中的细胞自主作用响应PDAC的肌肉浪费和功能障碍以及涉及的机制。我们预计我们的发现将阐明肌肉浪费的关键组织特异性机制和与癌症相关的无力，具有很高的翻译潜力。