Abstract 2657: Sex differences in pancreatic cancer cachexia manifestations and mechanisms in mice and humans: Role of activin
Authors: Zhong Xiaoling , Narasimhan Ashok , Young Andrew R. , Silverman Libbie M. , Liu Jianguo , Liu Sheng , Doud Emma H. , Wan Jun , Liu Yunlong , Mosley Amber L. , Koniaris Leonidas G. , Zimmers Teresa A. 
Published: July 2021

Abstract
Introduction: Cachexia is a metabolic syndrome leading to weight loss and muscle wasting. Pancreatic ductal adenocarcinoma (PDAC) frequently associates with cachexia, which contributes to its high mortality rate. Sex differences have been observed in cancer cachexia (Zhong and Zimmers, Curr Osteopor Rep 2020); however, the underlying molecular mechanisms are mostly unknown. We studied this here in both humans and mouse models. Because Activin is an important mediator of PDAC cachexia (Zhong et al., J Cachexia Sarcopenia Muscle 2019); thus, we also evaluated how sex affects anti-Activin treatment response.
Design: Mice: Male and female mice with autochthonic PDAC (KPC mice) were evaluated for cachexia phenotype and anti-Activin treatment response. Muscles were subjected to molecular and transcriptome/proteome analyses. Patients: Longitudinal change in body composition was measured retrospectively from CT scans of &gt;130 patients with PDAC treated with first-line gemcitabine/nab-paclitaxel and compared by sex. TCGA was queried for Activin gene expression versus mortality. Rectus abdominus muscles from PDAC patients were profiled for Activin pathway gene expression.
Results: Despite identical tumor latency and size, male KPC mice experienced earlier and more severe muscle wasting and responded positively to treatment with the Activin trap, ACVR2B/Fc, exhibiting muscle preservation, while female mice did not. Mediators and markers of muscle catabolism were increased in male KPC mice. RNAseq revealed increased muscle-specific E3 ligases, decreased myosin heavy chains, and inhibited canonical pathways in males with early cachexia, with fewer alterations in females. ACVR2B/Fc prevented many of these changes in late cachexia in males, but not in females, despite increased plasma Activin concentration in both sexes. Pathway analysis revealed sex-specific upstream regulators and mediators of muscle function. Muscle proteomics revealed impaired mitochondrial function in males only. Inhibitors of Activin-related ligands were upregulated in the muscle of female KPC mice only. Like mice, men with PDAC demonstrated greater loss of skeletal muscle area and index, and greater rate of muscle loss versus women. TCGA query revealed high tumor INHBA expression correlated with mortality, but only in men. Muscle from female patients with PDAC showed increased expression of Activin inhibitors, FSTL1, FSTL3, and WFIKKN2.
Conclusions: Male mice and cancer patients have higher prevalence of cachexia and greater muscle wasting compared with females. Furthermore, the Activin pathway mediates cachexia in a sex-specific fashion, potentially through muscle-specific expression of Activin inhibitors. These results demonstrate sex as the first premise for cachexia precision therapy.
Citation Format: Xiaoling Zhong, Ashok Narasimhan, Andrew R. Young, Libbie M. Silverman, Jianguo Liu, Sheng Liu, Emma H. Doud, Jun Wan, Yunlong Liu, Amber L. Mosley, Leonidas G. Koniaris, Teresa A. Zimmers. Sex differences in pancreatic cancer cachexia manifestations and mechanisms in mice and humans: Role of activin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2657.