D. Delitto1, S. M. Judge1, R. N. Nosacka1, T. J. George1, K. E. Behrns1, S. J. Hughes1, S. M. Wallet1, A. R. Judge1, J. G. Trevino1 1University Of Florida,Gainesville, FL, USA
Introduction: Pancreatic cancer (PC) is associated with a high rate of cachexia, which contributes significantly to patient morbidity and mortality. However, mechanisms underlying muscle wasting in the human disease remain incompletely described, in part due to limited translational models. We hypothesize that the development of translational models of pancreatic cancer cachexia will allow for the delineation of potential therapeutic targets in cachexia. To test our hypothesis, we propose to 1) establish the first described PDX model of cancer cachexia and 2) examine skeletal muscle in patients and corresponding patient-derived xenograft (PDX) models to further support a central role for transcription factors associated in PC-associated cachexia.
Methods: Rectus abdominis muscle was biopsied from surgically resected PC patients and non-cancer pancreatitis controls. Pancreatic cancer PDX models were derived in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice and skeletal muscle was harvested for histologic investigations on ultrastructural disorganization and qRT-PCR for atrophy-related transcription factors differentially regulated in PC patients.
Results: Rectus biopsies from patients with PC displayed marked muscle fiber atrophy, increased extracellular space, greater variation in fiber size and shape and more centralized nuclei compared to controls. These architectural abnormalities were also present in mice bearing xenografts representative patients with muscle wasting. Further, skeletal muscle from patients with PC and mice bearing PDX demonstrated high expression of the same Forkhead box O (FoxO)-dependent, atrophy-associated transcription factors.
Conclusions: Preoperative muscle wasting in PC is associated with characteristic architectural abnormalities and elevated FoxO-dependent transcriptional activity. Mice bearing patient-derived xenografts demonstrate comparable muscle pathology and transcriptional activity. These results thereby provide a valid translational model of cachexia which supports a central role for FoxO1 and FoxO3a in PC-associated muscle wasting.
