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

Abstract public domain (NIH RePORTER)

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 Unpublished work from our lab implicates a key role for Cellular Communication Network Factor 2 (CCN2), also known as connective tissue growth factor (CTGF), in mediating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

Public health relevance public domain (NIH RePORTER)

Project Narrative Cancer cachexia, which is particularly prevalent in pancreatic cancer, is a multifactorial syndrome that encompasses metabolic disruptions, hormonal abnormalities, and inflammation leading to negative energy balance and breakdown of muscle and adipose tissue. The breakdown of muscle tissue is particularly devastating because is negatively impacts physical function and quality of life, and also impacts patient’s ability to withstand the dose and frequency of aggressive conventional treatments for the disease and thus impacts survival. In the current work we will investigate the role of Cellular Communication Network Factor 2 (CCN2), also known as connective tissue growth factor (CTGF), which is produced by pancreatic tumors and in skeletal muscles in response to pancreatic cancer, in driving cachexia and muscle dysfunction.