Abstract 3483: 1H MRS characterization of the cachetic brain metabolome induced by human pancreatic pancer xenografts
Authors: Bharti Santosh Kumar , Winnard Paul T. , Mironchik Yelena , Penet Marie-France , Maitra Anirban , Bhujwalla Zaver M. 
Published: August 2018

The uncontrollable extreme weight loss due to cachexia results in a particularly poor quality of life causing profound weakness, listlessness, and an inability to function. A major characteristic of cachexia is accelerated skeletal muscle and fat storage wasting causing nutrient mobilization both directly as lipid and amino acids, and indirectly as ketone bodies and glucose derived from liver keto- and gluconeogenesis with systemic distribution including to the tumor through the bloodstream. Previously, we have reported the initial characterization of a myoblast optical imaging reporter that allowed real-time longitudinal monitoring of the early onset of cancer induced wasting and measured plasma metabolic changes associated with pancreatic ductal adenocarcinoma (PDAC)-induced cachexia. Here, for the first time, we have performed high-resolution quantitative 1H MR spectroscopy (MRS) of brain tissue to characterize the brain metabolome of normal mice and mice with human PDAC xenografts that induce cachexia (Pa04C cells) or are noncachectic (Panc1 cells).

Male severe combined immunodeficient mice were inoculated in the right flank with cancer cells (2×106) and in the right hind leg muscle with reporter myoblasts (2×106). Once the mice were sacrificed, brains were harvested, freeze clamped and stored in -80°C until 1H MRS analysis. Dual phase solvent extraction was performed on brain tissues and MR spectra were acquired on 750 MHz (17.6T) spectrometer.

As anticipated, mice with cachexia-inducing Pa04C tumors showed significant weight loss with time. For the first time, we found that brains from Pa04C tumor bearing mice exhibited a profound reduction in water soluble metabolites as compared to Panc1 and nontumor bearing normal mice. Significant decreases in neurotransmitters: γ-aminobutyric acid (GABA), N-acetyl aspartate (NAA), and taurine as well as lactate, myo-inositol, phosphocholine, glycerophosphocholine, creatine, formate, and essential amino acids: Leu, ILe, Val, and Phe were observed in brains from cachectic mice compared to noncachectic and healthy mice. Non-cachexia inducing Panc1 tumors also induced a significant decrease of brain GABA, glutamate, aspartate, total choline and tyrosine compared to normal brains. These results provide new insights into profound changes in brain metabolism during cachexia that are likely indicative of compromised CNS function and may be a major contributing factor to the systemic control of cachectic wasting. These data provide strong evidence to support investigating new metabolic interventions to reverse CNS injury and cachexia. and provide new CNS targets for early detection using in vivo MRS techniques.

Acknowledgement: This work was supported by NIH R01CA193365, R35CA209960, and P30CA06973.

Citation Format: Santosh Kumar Bharti, Paul T. Winnard, Yelena Mironchik, Marie-France Penet, Anirban Maitra, Zaver M. Bhujwalla. 1H MRS characterization of the cachetic brain metabolome induced by human pancreatic pancer xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3483.