Metabolic Imaging of Pancreatic Ductal Adenocarcinoma Detects Altered Choline Metabolism

Abstract

Purpose Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal disease that develops relatively symptom-free and is therefore advanced at the time of diagnosis. The absence of early symptoms and effective treatments has created a critical need for identifying and developing new noninvasive biomarkers and therapeutic targets. Experimental Design We investigated the metabolism of a panel of PDAC cell lines in culture and noninvasively in vivo with 1H magnetic resonance spectroscopic imaging (MRSI) to identify noninvasive biomarkers and uncover potential metabolic targets. Results We observed elevated choline-containing compounds in the PDAC cell lines and tumors. These elevated choline-containing compounds were easily detected by increased total choline (tCho) in vivo, in spectroscopic images obtained from tumors. Principal component analysis of the spectral data identified additional differences in metabolites between HPNE and neoplastic PDAC cells. Molecular characterization revealed overexpression of choline kinase (Chk)-α, choline transporter 1 (CHT1), and choline transporter-like protein 1 (CTL1) in the PDAC cell lines and tumors. Conclusions Collectively, these data identify new metabolic characteristics of PDAC and reveal potential metabolic targets. Total choline detected with 1H MRSI may provide an intrinsic, imaging-probe independent biomarker to complement existing techniques in detecting PDAC. The expression of Chk-α, CHT1, and CTL1 may provide additional molecular markers in aspirated cytological samples.

Choline Kinase Alpha (CHKα) as a Therapeutic Target in Pancreatic Ductal Adenocarcinoma: Expression, Predictive Value, and Sensitivity to Inhibitors

“…A recent study has shown high levels of choline and PC in PDAC cell lines and tumors, supporting the importance of CHKa as a potential metabolic target (32). Using bioinformatic analyses and a panel of cell lines, we show that CHKa is overexpressed in PDAC versus nontransformed HPDE pancreatic ductal epithelial cells, as has been reported in lung, breast, colorectal, and bladder cancer cells (11,14), and that PDAC lines rank among those expressing highest CHKa mRNA.…”

Effect of Pantethine on Ovarian Tumor Progression and Choline Metabolism

“…In the present study, we engrafted a piece of tumor tissue onto the ovary to avoid spilling of cancer cells and to maintain the tumor tissue microenvironment. We have used this technique in the past for prostate cancer (24) and for pancreatic cancer (25). In our model, ascites and metastases in the peritoneal cavity, in the liver, on the diaphragm, and in distal lymph nodes are frequent, similar to human disease, since ovarian carcinoma usually metastasizes along the peritoneum throughout the pelvic and abdominal cavity.…”

Detection of Pancreatic Cancer–Induced Cachexia Using a Fluorescent Myoblast Reporter System and Analysis of Metabolite Abundance

“…Human Panc1 (ATCC) and Pa04C cell lines (28, 29) were provided by Dr. Maitra of the Johns Hopkins University School of Medicine in 2012. The Panc1 cell line was established from a primary pancreatic ductal adenocarcinoma from a 56 year old male patient (30), and Pa04C was isolated from a lung metastasis in a 59 year old male patient with stage IV pancreatic adenocarcinoma (28).…”

“…Snap frozen muscle samples (40 to 70 mg) were powdered under liquid nitrogen, weighed, and dual phase extraction was performed, as described previously (29). Samples were reconstituted in 500 μl of 1× phosphate buffered D 2 O (90% D 2 O, 10% H 2 O, pH = 7.4), vortexed, centrifuged at 500g for 5 min at 4° C, and supernatants (450 µL) were subjected for 1 H MRS analysis.…”