Detection of Pancreatic Cancer–Induced Cachexia Using a Fluorescent Myoblast Reporter System and Analysis of Metabolite Abundance

Abstract

The dire effects of cancer-induced cachexia undermine treatment and contribute to decreased survival rates. Therapeutic options for this syndrome are limited, and therefore efforts to identify signs of precachexia in cancer patients are necessary for early intervention. The applications of molecular and functional imaging that would enable a whole-body “holistic” approach to this problem may lead to new insights and advances for diagnosis and treatment of this syndrome. Here we have developed a myoblast optical reporter system with the purpose of identifying early cachectic events. We generated a myoblast cell line expressing a dual tdTomato:GFP construct that was grafted onto the muscle of mice bearing human pancreatic cancer xenografts to provide noninvasive live imaging of events associated with cancer-induced cachexia (i.e., weight loss). Real time optical imaging detected a strong tdTomato fluorescent signal from skeletal muscle grafts in mice with weight loses of only 1.2 to 2.7% and tumor burdens of only ~79 to ~170 mm3. Weight loss in cachectic animals was also associated with a depletion of lipid, cholesterol, valine, and alanine levels, which may provide informative biomarkers of cachexia. Taken together, our findings demonstrate the utility of a reporter system that is capable of tracking tumor-induced weight loss, an early marker of cachexia. Future studies incorporating resected tissue from human pancreatic ductal adenocarcinoma (PDAC) into a reporter-carrying mouse may be able to provide a risk assessment of cachexia with possible implications for therapeutic development.

Brain metabolites in cholinergic and glutamatergic pathways are altered by pancreatic cancer cachexia

“…We have previously established that orthotopically or subcutaneously implanted Panc1 or Pa04C tumours exhibited metabolic profiles and weight patterns that were not implantation site dependent. 14,16 In the present study, brains of tumour-bearing mice weighed less than the brains of control mice, with cachectic mice showing on average a greater decrease of brain weight. However, when normalized to total body weight, the brains of cachectic mice were significantly higher in terms of percent body weight.…”

“…31 P and 1 H MR spectroscopy (MRS) have been used to investigate energy or metabolite changes in tumours, lymph nodes, livers, skeletal muscle, urine, and serum of cachectic animals and patients, but not cachectic brains. [13][14][15] As a result, little is known, outside of inflammation, about cachexia brain metabolic signatures. Such knowledge may expand our understanding of how changes in brain metabolism may contribute to cachectic progression and identify strategies to treat disrupted brain metabolism to restore CNS controlled peripheral metabolic homeostasis.…”

“…Comprehensive metabolomics of the brain based on ex‐vivo metabolite analyses of brain tissue from cachectic subjects have, however, not been reported. 31 P and 1 H MR spectroscopy (MRS) have been used to investigate energy or metabolite changes in tumours, lymph nodes, livers, skeletal muscle, urine, and serum of cachectic animals and patients, but not cachectic brains 13–15 . As a result, little is known, outside of inflammation, about cachexia brain metabolic signatures.…”

NMR‐based metabolomics of biofluids in cancer

“…Combined, these effects can modulate the metabolic state of many other organs, resulting in an altered global metabolic phenotype. This explains why for example inflammation and cachexia can be detected by metabolomics.…”

A randomized phase II study of nutritional and exercise treatment for elderly patients with advanced non-small cell lung or pancreatic cancer: the NEXTAC-TWO study protocol

“…We are also conducting a translational study to investigate new biomarkers for the diagnosis of cachexia. There is increasing evidence of a close link between cancer cachexia and plasma free amino acid (PFAA) or ghrelin levels [20, 21]. Cancer cachexia is characterized by skeletal muscle loss and anorexia [22].…”