Abstract
Pancreatic ductal adenocarcinoma (PDAC) patients display distinct phenotypes of cachexia development, with either adipose tissue loss preceding skeletal muscle wasting or loss of only adipose tissue. Activin A levels were measured in serum and analyzed in tumor specimens of both a cohort of Stage IV PDAC patients and the genetically engineered KPC mouse model. Our data revealed that serum activin A levels were significantly elevated in Stage IV PDAC patients in comparison to age-matched non-cancer patients. Little is known about the role of activin A in adipose tissue wasting in the setting of PDAC cancer cachexia. We established a correlation between elevated activin A and remodeling of visceral adipose tissue. Atrophy and fibrosis of visceral adipose tissue was examined in omental adipose tissue of Stage IV PDAC patients and gonadal adipose tissue of an orthotopic mouse model of PDAC. Remarkably, white visceral adipose tissue from both PDAC patients and mice exhibited decreased adipocyte diameter and increased fibrotic deposition. Strikingly, expression of thermogenic marker UCP1 in visceral adipose tissues of PDAC patients and mice remained unchanged. Thus, we propose that activin A signaling could be relevant to the acceleration of visceral adipose tissue wasting in PDAC-associated cachexia.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) patients display distinct phenotypes of cachexia development, with either adipose tissue loss preceding skeletal muscle wasting or loss of only adipose tissue
Visceral adipose tissue loss can be correlated with increasing systemic activin A levels con‐ tributed by pancreatic ductal adenocarcinoma (PDAC) tumors
We first analyzed the correlation between INHBA expression and the prevalence of cancer cachexia in 18 types of cancer using RNA-Seq data from The Cancer Genome Atlas (TCGA)
Summary
Pancreatic ductal adenocarcinoma (PDAC) patients display distinct phenotypes of cachexia development, with either adipose tissue loss preceding skeletal muscle wasting or loss of only adipose tissue. One recent report demonstrates that subcutaneous adipose tissue loss is initiated in patients prior to loss of skeletal muscle and PDAC diagnosis, identifying three distinct and progressive phases of metabolic and soft tissue changes in pre-diagnostic PDAC starting up to 18 months before d iagnosis[11]. This phenomenon insinuates that a causal factor for cachexia has already begun to exert systemic effects prior to presentation of prominent cachectic symptoms. Factors that mediate adipose tissue loss in PDAC patients and their contribution to WAT browning in PDAC-mediated cachexia remain to be unveiled
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