Spatiotemporal Proteomic Analyses during Pancreas Cancer Progression Identifies Serine/Threonine Stress Kinase 4 (STK4) as a Novel Candidate Biomarker for Early Stage Disease

Abstract

Pancreas cancer, or pancreatic ductal adenocarcinoma, is the deadliest of solid tumors, with a five-year survival rate of <5%. Detection of resectable disease improves survival rates, but access to tissue and other biospecimens that could be used to develop early detection markers is confounded by the insidious nature of pancreas cancer. Mouse models that accurately recapitulate the human condition allow disease tracking from inception to invasion and can therefore be useful for studying early disease stages in which surgical resection is possible. Using a highly faithful mouse model of pancreas cancer in conjunction with a high-density antibody microarray containing ϳ2500 antibodies, we interrogated the pancreatic tissue proteome at preinvasive and invasive stages of disease. The goal was to discover early stage tissue markers of pancreas cancer and follow them through histologically defined stages of disease using cohorts of mice lacking overt clinical signs and symptoms and those with end-stage metastatic disease, respectively. A panel of seven up-regulated proteins distinguishing pancreas cancer from normal pancreas was validated, and their levels were assessed in tissues collected at preinvasive, early invasive, and moribund stages of disease. Six of the seven markers also differentiated pancreas cancer from an experimental model of chronic pancreatitis. The levels of serine/threonine stress kinase 4 (STK4) increased between preinvasive and invasive stages, suggesting its potential as a tissue biomarker, and perhaps its involvement in progression from precursor pancreatic intraepithelial neoplasia to pancreatic ductal adenocarcinoma. Immunohistochemistry of STK4 at different stages of disease revealed a dynamic expression pattern further implicating it in early tumorigenic events. Immunohistochemistry of a panel of human pancreas cancers confirmed that STK4 levels were increased in tumor epithelia relative to normal tissue. Overall, this integrated approach yielded several tissue markers that could serve as signatures of disease stage, including early (resectable), and therefore clinically meaningful, stages. Molecular & Cellular Proteomics

Cross-Species Antibody Microarray Interrogation Identifies a 3-Protein Panel of Plasma Biomarkers for Early Diagnosis of Pancreas Cancer

“…In the present study, we used our high density antibody microarray platform (8–10) customized for pancreas cancer (11), to interrogate: 1) plasma drawn at distinct time points from a highly faithful genetically engineered mouse model of pancreas cancer (12); 2) pre-diagnostic plasma from women who later succumbed to PDA; and 3) diagnostic plasma from patients. By further focusing on identified plasma membrane and secreted proteins, we identified two markers that overlapped between mouse and pre-diagnostic human datasets and that have individually been previously implicated in PDA; a third novel marker, ESR1, was identified by multiple distinct antibodies in pre-diagnostic human plasma samples.…”

Discovery of novel plasma proteins as biomarkers for the development of incisional hernias after midline incision in patients with colorectal cancer: The ColoCare study

“…32 Briefly, for each antibody feature, the fold change of case and control signal (red channel) relative to the reference (green channel) was calculated as log 2 ( R c / G c ), where R c is red corrected and G c is green corrected applying a normexp background correction method. 33 Paired t-test was performed to assess the difference between case and control signal for each antibody.…”

The Pathogenesis, Diagnosis, and Management of Pancreatic Cancer

“…The histological progressive genetic model suggests that the molecular detection of precursor lesions and early cancers is possible as mutant K-ras genes shed from PanINs have been identified in stool, duodenal fluid, and pancreatic juice samples [21]. Research is attempting to identify markers in pancreatic fluid that could reliably identify high-grade PanINs [34].…”

“…The histological progressive genetic model suggests that the molecular detection of precursor lesions and early cancers is possible as mutant K-ras genes shed from PanINs have been identified in stool, duodenal fluid, and pancreatic juice samples [21]. Research is attempting to identify markers in pancreatic fluid that could reliably identify high-grade PanINs [34].Adenosquamous carcinoma is a rare variant of ductal adenocarcinoma that shows both glandular and squamous differentiation [35]. This variant appears to be more common in patients who have undergone previous chemoradiation therapy.…”