title: 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 ∼2500 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.
authors.affiliation: From the ‡Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109; §Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109;
authors.forename: Justin E
authors.initials: JE
authors.lastname: Mirus
authors.affiliation: From the ‡Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109;
authors.forename: Yuzheng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: ¶Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198;
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hollingsworth
authors.affiliation: From the ‡Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109; §Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109;
authors.forename: Joell L
authors.initials: JL
authors.lastname: Solan
authors.affiliation: From the ‡Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109; §Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109; plampe@fhcrc.org srh@fhcrc.org.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Lampe
authors.affiliation: From the ‡Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109; **Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109; ‡‡Division of Medical Oncology, University of Washington School of Medicine, Seattle, Washington 98195 plampe@fhcrc.org srh@fhcrc.org.
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Hingorani
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002108:Ceruletide; D003937:Diagnosis, Differential; D004195:Disease Models, Animal; D018450:Disease Progression; D042241:Early Diagnosis; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D058977:Molecular Sequence Annotation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D040081:Protein Array Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D000099317:Hippo Kinases
chemical_list: D000906:Antibodies; D014408:Biomarkers, Tumor; D002108:Ceruletide; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D020543:Proteome; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases