Pancreatic cancer induces muscle wasting by promoting the release of pancreatic adenocarcinoma upregulated factor

Young Hoon Son,Kyung Won Kim,Seongyea Jo,Dana Jung,Yeon Jeong Kim,Yousun Ko,Yong Ryoul Yang,Wonbeak Yoo,Jaemin Lee,Kyung Hee Noh,Sang Seok Koh,Song Cheol Kim,Eunsung Jun,Hyunji Choi,Seokho Kim,Eun-Soo Kwon,Kwang-Pyo Lee

doi:10.1038/s12276-021-00582-2

Abstract

Cancer cachexia is a highly debilitating condition characterized by weight loss and muscle wasting that contributes significantly to the morbidity and mortality of pancreatic cancer. The factors that induce cachexia in pancreatic cancer are largely unknown. We previously showed that pancreatic adenocarcinoma upregulated factor (PAUF) secreted by pancreatic cancer cells is responsible for tumor growth and metastasis. Here, we analyzed the relation between pancreatic cancer-derived PAUF and cancer cachexia in mice and its clinical significance. Body weight loss and muscle weight loss were significantly higher in mice with Panc-1/PAUF tumors than in those with Panc-1/Mock tumors. Direct administration of rPAUF to muscle recapitulated tumor-induced atrophy, and a PAUF-neutralizing antibody abrogated tumor-induced muscle wasting in Panc-1/PAUF tumor-bearing mice. C2C12 myotubes treated with rPAUF exhibited rapid inactivation of Akt-Foxo3a signaling, resulting in Atrogin1/MAFbx upregulation, myosin heavy chain loss, and muscle atrophy. The neutrophil-to-lymphocyte ratio and body weight loss were significantly higher in pancreatic cancer patients with high PAUF expression than in those with low PAUF expression. Analysis of different pancreatic cancer datasets showed that PAUF expression was significantly higher in the pancreatic cancer group than in the nontumor group. Analysis of The Cancer Genome Atlas data found associations between high PAUF expression or a high DNA copy number and poor overall survival. Our data identified tumor-secreted circulating PAUF as a key factor of cachexia, causing muscle wasting in mice. Neutralizing PAUF may be a useful therapeutic strategy for the treatment of pancreatic cancer-induced cachexia.

Highlights

Cachexia is a metabolic syndrome characterized by decreases in skeletal muscle and fat that occurs in more than 50% of patients with advanced solid cancers[1]
Mice inoculated with Panc-1/pancreatic adenocarcinoma upregulated factor (PAUF) cells showed a decrease in total body weight without changes in food consumption (Supplementary Materials, Fig. s2b, c)
These results indicate that tumor formation by PAUF-expressing cells results in overall body weight loss because of cachexia in mice

Summary

Introduction

Cachexia is a metabolic syndrome characterized by decreases in skeletal muscle and fat that occurs in more than 50% of patients with advanced solid cancers[1]. The clinical features of cachexia include weight loss, Up to 80% of pancreatic cancer patients develop cachexia during the disease course[6]. Yoo et al Experimental & Molecular Medicine (2021) 53:432–445 pancreatic cancer patients die from complications of cachexia, including severe respiratory muscle damage because of cardiopulmonary dysfunction and immune dysfunction[7]. More than 70% of newly diagnosed pancreatic cancer patients meet cachexia criteria, and nearly 70% of pancreatic cancers are diagnosed as unresectable, pancreatic cancer patients who undergo resection show cachexia, and 40% of patients eligible for resection show weight loss[8]. Even in patients who undergo resection, cachexia is associated with poor responses to treatment and decreased survival rates. The identification of a cancer cachexiaassociated biomarker would be valuable to improve the outcomes of pancreatic cancer patients

Methods

Results

Conclusion