Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development

Abstract

Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months1. PDAC has been linked with obesity and glucose intolerance2-4, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from pancreatic cancer cases and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched chain amino acids (BCAAs) are associated with a greater than 2–fold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years prior to diagnosis when occult disease is likely present. We show that plasma BCAAs are also elevated in mice with early stage pancreatic cancers driven by mutant Kras expression, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early stage disease. Together, these findings suggest that increased whole–body protein breakdown is an early event in development of PDAC.

Sequential Validation of Blood-Based Protein Biomarker Candidates for Early-Stage Pancreatic Cancer

“…Further validation of the three-marker panel in independent prediagnostic cohorts will be required to demonstrate utility for pancreatic cancer screening, leading to the development of an US Food and Drug Administration-approved test for targeted screening populations. Moreover, further improvement in marker performance may result from inclusion in the panel of additional marker types other than circulating proteins (15)(16)(17)(18)(19)(20)(21)(22)46) through critical testing of marker combinations. …”

“…As a result, there is substantial ongoing effort to identify additional serological biomarkers that complement CA19-9 for the detection of early-stage PDAC. Markers investigated include proteins (9)(10)(11)(12)(13)(14), metabolites (15)(16)(17), autoantibodies (18,19), miRNAs (20)(21)(22), markers with aberrant glycosylation (CA19-9 and Tn antigens) (6,23,24), and exosomes (25). In view of the wide array of potential biomarkers, there is a need for systematic evaluation of candidates using CA19-9 as an anchor marker given its established performance.…”

Nature and Nurture: What Determines Tumor Metabolic Phenotypes?

“…Elevated plasma branched chain amino acids (BCAA) were identified as an early event in pancreatic ductal adenocarcinoma (PDAC) in both mice and humans, a whole body metabolic change that results from increased muscle protein turnover in individuals with this cancer (29). To determine whether the BCAA elevation was unique to PDAC, isogenic mouse models of PDAC and non-small cell lung carcinoma (NSCLC) that are driven by both activating Kras mutations and Trp53 disruption were analyzed, and in contrast to mice with early PDAC, mice with early NSCLC had decreased levels of plasma BCAAs (30).…”

Regulation of the plasma amino acid profile by leucine via the system L amino acid transporter

“…Rather, the leucine action, which may stimulate the amino acid influx into cells from the circulation, may contribute to increase the availability of amino acids for protein synthesis in cells. From a clinical point of view, it is important to clarify the regulation of plasma amino acid profiles, especially plasma BCAA concentrations, because these changes are associated with the onset and development of diseases such as hepatocarcinogenesis associated with liver cirrhosis, 26) pancreatic adenocarcinoma, 27) and diabetes associated with insulin resistance. 2) Further detailed studies on the regulation of amino acid profiles will contribute to the diagnosis and treatment of these diseases.…”