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

摘要/摘要 癌症相关性恶病质是一种多因素综合征，其特征是身体不由自主地丧失和 降低对癌症治疗的耐受性的骨骼肌群(有或没有脂肪损失)会增加 手术后的并发症，并强烈预测存活率下降。然而，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，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 CCN2，也称为结缔组织生长因子(CTGF)，在介导胰腺恶病质中的作用 导管腺癌(PDAC)是一种恶病质发生率较高的癌症类型。结缔组织生长因子是一种低氧诱导因子 胰腺癌细胞和PDAC肿瘤产生的局部功能诱导的基质细胞蛋白 间质重塑、肿瘤生长和转移。在PDAC小鼠模型中，我们发现CTGF和HIF1a 在肿瘤中上调的时间点对应于恶病质的开始和进展，提示CTGF 缺氧性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的基因或药物靶向抑制恶病质，阻断宿主和肿瘤细胞分泌 恶病质的关键循环介质，尽管控制了CTGF对肿瘤生长的依赖作用，但领先 美国假设CTGF至少部分通过促进细胞因子依赖促进PDAC恶病质 在外周组织中的信号，这将在目标1中进行研究。除了PDAC中CTGF的产生 在肿瘤中，CTGF也在恶病质患者和患有PDAC的小鼠的骨骼肌中上调。因此，我们 假设肌肉组织中局部产生的CTGF也可能在肌肉萎缩中发挥直接作用 对PDAC的反应，通过使用AAV将CTGF-shRNA靶向肌肉组织来支持。穿过 单核RNAseq我们进一步发现CTGF在呼吸系统和外周骨骼中表达上调 PDAC小鼠的肌肉以细胞类型特异的方式表达，CTGF通常在一个亚群中上调 显示萎缩相关基因表达增加的成熟骨骼肌核。在体外使用两者 在活体模型中，Aim 2将进一步研究CTGF在介导骨骼组织中的细胞自主作用 PDAC引起的肌肉萎缩和功能障碍，以及相关的机制。我们预计我们的 这些发现将阐明与癌症相关的肌肉萎缩和虚弱的关键组织特异性机制， 具有很高的翻译潜力。

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 Unpublished work from our lab implicates a key role for Cellular Communication Network Factor 2 (CCN2), also known as connective tissue growth factor (CTGF), in mediating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.