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

• 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
• 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skeletal muscle wasting; small hairpin RNA; transcriptome sequencing; translational potential; tumor; tumor growth; unpublished works; vector

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 癌症相关恶病质是一种多因素综合征，其特征是身体和功能的不自觉丧失。 骨骼肌质量（有或没有脂肪减少）会降低对癌症治疗的耐受性，增加 手术后出现并发症，强烈预示着生存率降低。不过，目前还没有 保留或逆转癌症患者肌肉质量损失的有效疗法，凸显了重大差距 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 （CCN2），也称为结缔组织生长因子（CTGF），介导胰腺引起的恶病质 导管腺癌（PDAC），一种恶病质患病率较高的癌症类型。 CTGF是一种缺氧诱导的 由胰腺癌细胞和 PDAC 肿瘤产生的基质细胞蛋白，其局部功能可诱导 基质重塑、肿瘤生长和转移。在 PDAC 小鼠模型中，我们发现 Ctgf 和 Hif1a 在与恶病质发生和进展相对应的时间点，肿瘤中 CTGF 上调，表明 CTGF 缺氧 PDAC 肿瘤的产生也可能与恶病质有关。在初步研究中我们发现 CTGF 的遗传或药理学靶向可抑制恶病质并阻止宿主和肿瘤细胞分泌 尽管控制了CTGF对肿瘤生长的依赖性影响，但恶病质的关键循环介质仍导致 我们假设 CTGF 至少部分通过促进细胞因子依赖性来促进 PDAC 恶病质 外周组织中的信号传导，这将在目标 1 中进行研究。除了 PDAC 内的 CTGF 产生之外 在恶病质患者和患有 PDAC 的小鼠的骨骼肌中，CTGF 也上调。我们因此 假设肌肉组织内 CTGF 的局部产生也可能在肌肉萎缩中发挥直接作用 对 PDAC 的反应，这是通过使用 AAV 将 Ctgf-shRNA 靶向肌肉组织来支持的。通过 单核 RNAseq 我们进一步确定 Ctgf 在呼吸和外周骨骼中上调 PDAC 小鼠的肌肉以细胞类型特异性方式变化，Ctgf 在亚群内通常上调 成熟骨骼肌细胞核显示萎缩相关基因表达增加。体外同时使用 和体内模型，Aim 2 将进一步研究 Ctgf 在介导骨骼肌中的细胞自主作用 PDAC 引起的肌肉萎缩和功能障碍及其相关机制。我们预计我们的 研究结果将阐明与癌症相关的肌肉萎缩和无力的关键组织特异性机制， 具有很高的转化潜力。