Abstract 1625: Lung and kidney metabolism altered by cancer-induced cachexia

Introduction: Cachexia is a complex metabolic syndrome that affects nearly 80% of pancreatic ductal adenocarcinoma (PDAC) patients. Major symptoms of cancer induced cachexia include loss of skeletal muscle weight with or without fat loss and reduced physical activity [1, 2]. Cancer cachexia may lead to multiple organ dysfunction and metabolic abnormalities [3]. To date there are no known cures for this condition. Our ongoing studies have focused on understanding the metabolic impact of PDAC induced cachexia in vital organs using 1H magnetic resonance spectroscopy (MRS) of organ extracts to expand our understanding of this syndrome. Here we have focused on understanding the metabolic changes occurring in the lungs and kidneys using our well established PDAC xenograft models. We compared organ changes in mice with cachexia-inducing xenografts (Pa04C) to mice with non-cachexia-inducing xenografts (Panc1) and normal mice. We have previously established significant weight loss in Pa04C tumor bearing mice compared to Panc1 tumor bearing mice [4]. Methods: Panc1 cells were obtained from ATCC and Dr. Maitra kindly provided Pa04C cells. Cancer cells were inoculated in the right flank of six to eight week old male severe combined immunodeficient mice. Kidneys and lungs from normal mice and from Pa04C and Panc1 tumor bearing mice (n=5 per group), excised from euthanized mice once tumors were ~300 mm3, were snap frozen and stored at -80°C prior to dual phase extraction. 1H MRS was performed on the water phase. All 1H MR spectra were acquired on a 750 MHz MR spectrometer. All data processing analyses and quantification were performed with TOPSPIN 3.5 software. Statistical analysis was performed with MetaboAnalyst software [5]. Result and Discussion Multivariate principal component analysis of lung and kidney data identified a clear separation between the Pa04C tumor-bearing group compared to the Panc1 tumor bearing group and normal mice. Significant differences in several metabolites were observed in the lungs and kidneys of Pa04C tumor bearing mice compared to Panc1 tumor bearing mice and normal mice. Significant metabolic differences were detected in amino acids, BCAA, glutathione, acetate, histidine, phenylalanine and tyrosine in the lung and kidney. These metabolic changes can influence the function of these organs. Our results support an expanded understanding of the changes in organ metabolism that may occur with cancer-induced cachexia and with cancer in general that may contribute to morbidity and poor treatment response. Acknowledgement: This work was supported by NIH R35CA209960 and R01CA193365. Ref: 1. Fearon K et al, The Lancet Oncology. 2011; 2. Penet MF, Bhujwalla ZM. Cancer journal. 2015; 3. Argiles JM et al, Nature reviews Cancer. 2014; 4. Winnard PT, Jr. et al, Cancer research. 2016; 5. Xia J, Wishart DS. Nature protocols. 2011. Citation Format: Raj Kumar Sharma, Santosh K. Bharti, Paul T. Winnard, Marie-France Penet, Zaver M. Bhujwalla. Lung and kidney metabolism altered by cancer-induced cachexia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1625.