Identification of Potential Serum Protein Biomarkers and Pathways for Pancreatic Cancer Cachexia Using an Aptamer-Based Discovery Platform

Abstract

Patients with pancreatic ductal adenocarcinoma (PDAC) suffer debilitating and deadly weight loss, known as cachexia. Development of therapies requires biomarkers to diagnose, and monitor cachexia; however, no such markers are in use. Via Somascan, we measured ~1300 plasma proteins in 30 patients with PDAC vs. 11 controls. We found 60 proteins specific to local PDAC, 46 to metastatic, and 67 to presence of >5% cancer weight loss (FC ≥ |1.5|, p ≤ 0.05). Six were common for cancer stage (Up: GDF15, TIMP1, IL1RL1; Down: CCL22, APP, CLEC1B). Four were common for local/cachexia (C1R, PRKCG, ELANE, SOST: all oppositely regulated) and four for metastatic/cachexia (SERPINA6, PDGFRA, PRSS2, PRSS1: all consistently changed), suggesting that stage and cachexia status might be molecularly separable. We found 71 proteins that correlated with cachexia severity via weight loss grade, weight loss, skeletal muscle index and radiodensity (r ≥ |0.50|, p ≤ 0.05), including some known cachexia mediators/markers (LEP, MSTN, ALB) as well as novel proteins (e.g., LYVE1, C7, F2). Pathway, correlation, and upstream regulator analyses identified known (e.g., IL6, proteosome, mitochondrial dysfunction) and novel (e.g., Wnt signaling, NK cells) mechanisms. Overall, this study affords a basis for validation and provides insights into the processes underpinning cancer cachexia.

Tumor-derived IL-6 and trans-signaling among tumor, fat, and muscle mediate pancreatic cancer cachexia

“…These discrepancies with observations in mouse models, including our own, might relate to the difficulty of detecting the many forms of IL-6 in circulation, both unbound and bound to sIL6R and sGP130, rather than reflecting the absence of IL-6 activity ( Chaturvedi et al, 2015 ). Indeed, a proteomic signature of IL-6 activity correlates to cachexia severity in patients with PDAC ( Narasimhan et al, 2020 ). Alternatively, tissue levels of IL-6 and its signaling components might be both more relevant as biomarkers and more important for initiating wasting.…”

Biomarkers for Cancer Cachexia: A Mini Review

“…In a study investigating the association of plasma TIMP-1 level with cachexia in pancreatic cancer patients, elevated TIMP-1 levels were found in patients with weight loss and without jaundice [ 99 ]. However, in another study using an aptamer-based discovery platform to identify serum protein biomarkers for pancreatic cancer cachexia, TIMP-1 was only associated with stages of cancer but not weight loss [ 109 ]. Previously identified biomarkers such as GDF15 did not show significant correlation with weight loss in pancreatic cancer patients in this study [ 109 ].…”

“…However, in another study using an aptamer-based discovery platform to identify serum protein biomarkers for pancreatic cancer cachexia, TIMP-1 was only associated with stages of cancer but not weight loss [ 109 ]. Previously identified biomarkers such as GDF15 did not show significant correlation with weight loss in pancreatic cancer patients in this study [ 109 ].…”

Ketogenic Diets in Pancreatic Cancer and Associated Cachexia: Cellular Mechanisms and Clinical Perspectives

“…Because chemotherapeutic doses are determined by body weight or surface area, patients with a lean body mass (LBM) equivalent to underweight are more susceptible to suffering toxicities [ 29 ]. Cachexia is associated with chemotherapy toxicity, functional impairment, surgery complications, and mortality [ 30 , 31 ]. For these reasons, the preservation of SKM is extremely important [ 32 ].…”