Abstract
Simple SummaryMore than 80% of patients with pancreatic ductal adenocarcinoma (PDAC) suffer cachexia, characterized by loss of muscle and fat. However, most cachexia studies were predominantly focused on muscle. Our clinical study showed adipose tissue loss as a prognosticator in PDAC cachexia. Our study aims to understand the concurrent muscle and adipose changes using transcriptome profiling. We identified tissue-specific gene expression profiles with changes in adipose being more dynamic. Pathway analysis suggests that muscle and adipose wasting may be mediated through independently targetable mechanisms which may have therapeutic implications. Many of the well-known and novel cachexia genes have been validated using an external muscle and adipose datasets. The study provides the groundwork for future studies to understand if fat wasting precedes muscle wasting in PDAC and if adipose can be targeted for therapeutic interventions. The study also shows that age related muscle loss has distinct mechanisms compared to cachexia.The vast majority of patients with pancreatic ductal adenocarcinoma (PDAC) suffer cachexia. Although cachexia results from concurrent loss of adipose and muscle tissue, most studies focus on muscle alone. Emerging data demonstrate the prognostic value of fat loss in cachexia. Here we sought to identify the muscle and adipose gene profiles and pathways regulated in cachexia. Matched rectus abdominis muscle and subcutaneous adipose tissue were obtained at surgery from patients with benign conditions (n = 11) and patients with PDAC (n = 24). Self-reported weight loss and body composition measurements defined cachexia status. Gene profiling was done using ion proton sequencing. Results were queried against external datasets for validation. 961 DE genes were identified from muscle and 2000 from adipose tissue, demonstrating greater response of adipose than muscle. In addition to known cachexia genes such as FOXO1, novel genes from muscle, including PPP1R8 and AEN correlated with cancer weight loss. All the adipose correlated genes including SCGN and EDR17 are novel for PDAC cachexia. Pathway analysis demonstrated shared pathways but largely non-overlapping genes in both tissues. Age related muscle loss predominantly had a distinct gene profiles compared to cachexia. This analysis of matched, externally validate gene expression points to novel targets in cachexia.
Highlights
Cancer associated cachexia is a debilitating multifactorial syndrome characterized by involuntary loss of muscle and fat [1,2,3,4]
Several common pathways were identified between muscle and adipose, the genes involved in these pathways are predominantly different, suggesting that adipose and muscle wasting may be mediated by independent mechanisms
A similar inference cannot be made from the adipose correlation as this is the first study to profile adipose tissue from a homogeneous cohort and the second overall in the literature to profile human genes associated with fat wasting in cachexia
Summary
Cancer associated cachexia is a debilitating multifactorial syndrome characterized by involuntary loss of muscle and fat [1,2,3,4]. The pathophysiology of PDAC cachexia involves a complex interplay between the host and tumor interactions which results in inflammation, malnutrition, anorexia, and neuroendocrine changes. These complex interactions lead to a series of metabolic changes including. PDAC and understand cachexia mechanisms [19,20]. Most of our understanding about cachexia comes from muscle, it is known that cachexia often involves wasting of fat [4,21,22,23,24]. The molecular mechanisms of fat wasting in PDAC cachexia are less explored
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