Most patients with pancreatic adenocarcinoma (PDAC) suffer cachexia; some do not. To model heterogeneity, we used patient-derived orthotopic xenografts. These phenocopied donor weight loss. Furthermore, muscle wasting correlated with mortality and murine IL-6, and human IL-6 associated with the greatest murine cachexia. In cell culture and mice, PDAC cells elicited adipocyte IL-6 expression and IL-6 plus IL-6 receptor (IL6R) in myocytes and blood. PDAC induced adipocyte lipolysis and muscle steatosis, dysmetabolism, and wasting. Depletion of IL-6 from malignant cells halved adipose wasting and abolished myosteatosis, dysmetabolism, and atrophy. In culture, adipocyte lipolysis required soluble (s)IL6R, while IL-6, sIL6R, or palmitate induced myotube atrophy. PDAC cells activated adipocytes to induce myotube wasting and activated myotubes to induce adipocyte lipolysis. Thus, PDAC cachexia results from tissue crosstalk via a feed-forward, IL-6 trans-signaling loop. Malignant cells signal via IL-6 to muscle and fat, muscle to fat via sIL6R, and fat to muscle via lipids and IL-6, all targetable mechanisms for treatment of cachexia.

Background Cachexia is frequent, deadly, and untreatable for patients with pancreatic ductal adenocarcinoma (PDAC). The reproductive hormone and cytokine Activin is a mediator of PDAC cachexia, and Activin receptor targeting was clinically tested for cancer cachexia therapy. However, sex‐specific manifestations and mechanisms are poorly understood, constraining development of effective treatments. Methods Cachexia phenotypes, muscle gene/protein expression, and effects of the Activin blocker ACVR2B/Fc were assessed in LSL‐KrasG12D/+, LSL‐Trp53R172H/+, and Pdx‐1‐Cre (KPC) mice with autochthonic PDAC. Effects of PDAC and sex hormones were modelled by treating C2C12 myotubes with KPC‐cell conditioned medium (CM) and estradiol. Muscle gene expression by RNAseq and change in muscle from serial CT scans were measured in patients with PDAC. Results Despite equivalent tumour latency (median 17 weeks) and mortality (24.5 weeks), male KPC mice showed earlier and more severe cachexia than females. In early PDAC, male gastrocnemius, quadriceps, and tibialis anterior muscles were reduced (−21.7%, −18.9%, and −20.8%, respectively, all P < 0.001), with only gastrocnemius reduced in females (−16%, P < 0.01). Sex differences disappeared in late PDAC. Plasma Activin A was similarly elevated between sexes throughout, while oestrogen and testosterone levels suggested a virilizing effect of PDAC in females. Estradiol partially protected myotubes from KPC‐CM induced atrophy and promoted expression of the potential Activin inhibitor Fstl1. Early‐stage female mice showed greater muscle expression of Activin inhibitors Fst, Fstl1, and Fstl3; this sex difference disappeared by late‐stage PDAC. ACVR2B/Fc initiated in early PDAC preserved muscle and fat only in male KPC mice, with increases of 41.2%, 52.6%, 39.3%, and 348.8%, respectively, in gastrocnemius, quadriceps, tibialis, and fat pad weights vs. vehicle controls, without effect on tumour. No protection was observed in females. At protein and RNA levels, pro‐atrophy pathways were induced more strongly in early‐stage males, with sex differences less evident in late‐stage disease. As with mass, ACVR2B/Fc blunted atrophy‐associated pathways only in males. In patients with resectable PDAC, muscle expression of Activin inhibitors FSTL1, FSLT3, and WFIKKN2/GASP2 were higher in women than men. Overall, among 124 patients on first‐line gemcitabine/nab‐paclitaxel for PDAC, only men displayed muscle loss (P < 0.001); average muscle wasting in men was greater (−6.63 ± 10.70% vs. −1.62 ± 12.00% mean ± SD, P = 0.038) and more rapid (−0.0098 ± 0.0742%/day vs. −0.0466 ± 0.1066%/day, P = 0.017) than in women. Conclusions Pancreatic ductal adenocarcinoma cachexia displays sex‐specific phenotypes in mice and humans, with Activin a preferential driver of muscle wasting in males. Sex is a major modulator of cachexia mechanisms. Consideration of sexual dimorphism is essential for discovery and development of effective treatments.

Background/Objective:  Low muscle mass (myopenia), poor muscle quality, myosteatosis, and muscle loss are associated with mortality in solid tumors. However, their impact in hematological malignancies remains unclear. We sought to determine how muscle phenotype relates to survival in patients with multiple myeloma.  Methods:  We performed a retrospective review of patients with multiple myeloma treated at Indiana University Hospital from 2012-2016. Total skeletal muscle area (SMA) (cm2) and radiodensity were measured on baseline (closest to diagnosis) and last CT scans at the third lumbar vertebrae area. SMA was normalized to height (SMA cm2/m2) to define skeletal muscle index (SKMI). Myopenia was defined as (SKMI) <52.4 cm2/m2 (men) and <38.5 cm2/m2 (women). Myosteatosis and obesity were defined per published BMI-specific cutoffs. Difference in survival between groups was estimated using log rank test.   Results:  Of 455 patients with multiple myeloma, 137 had more than one CT scan; 42 of these have been assessed to date. Half (21/42) were myopenic. Myopenia was equally prevalent across BMI categories and showed no association with survival. More than half of patients displayed myostetatosis; however, this was not associated with survival.  Obesity and myopenic obesity were likewise not correlated with survival. Below-median baseline SKMI correlated with mortality, HR 2.721 (95% CI, 1.160-5.564: P=0.0129). As well, below-median final SMA correlated with mortality, HR 2.381 (95% CI, 1.094-5.181, P=0.0213). On average patients lost .7129% of SMA (95% CI; -6.072%-4.646%). Females had higher mortality, HR 2.355 (95% CI 0.9895-5.604, P=0.0215).   Conclusion and Potential Impact:  Although this study represents a fraction of treated patients to date, myopenia was prevalent among patients at diagnosis of multiple myeloma. Low muscle mass and sex appear to be important prognostic factors for survival. Additional measurements as well as univariate and multivariate analyses are necessary to verify these findings and identify additional factors that contribute to survival in multiple myeloma.

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.