Analysis of disseminated tumor cells to characterize minimal residual disease in patients with surgically resectable pancreatic cancer

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Pancreatic ductal adenocarcinoma, the most common subtype of pancreatic cancer, is a disease with dismal 5-year survival reaching about 9%. This dire prognosis largely attributed to late diagnosis, aggressiveness and treatment resistance. If diagnosed early at a localized stage, surgical resection combined with chemotherapy is the favored treatment option with the best curative chance. However, the specific biology of the tumor with a high propensity to metastasize into distant organs is the prognosis-limiting step. Even after complete margin-free resection of the tumor, recurrence occurs in about 75% of patients within two years (most often in the liver). This suggests the hypothesis that systemic spread of disseminated tumor cells (DTCs) in the body which are left behind after surgery cause the growth of metastases in these patients. This postoperative condition is referred to as minimal residual disease.Current research publications confirm the existence of DTCs in pancreatic cancer in bone marrow and liver. Insights into biological properties and the genetic composition of minimal residual disease are still widely limited, but crucial for individual postoperative risk stratification of patients and future development of targeted therapies to improve prognosis and survival outcomes.During the research fellowship, DTCs in the bone marrow and liver will be analyzed in samples taken at the time of surgery. After identification of the tumor cells, immunocytochemistry will be used to investigate the expression of selected proteins. Markers for epithelial, transitional or mesenchymal differentiation represent the potential of the cells to trigger growth of a metastasis. Surface molecules with evidence of immune tolerance (MHC class I, PD-L1) are analyzed. Furthermore, molecular genetic analyses will be performed to map the expression of mutated gene sequences at the RNA level of the cells (next-generation sequencing). The aim of the experiments is to characterize minimal residual disease in pancreatic cancer comprehensively to generate profiles of systemic tumor biology. In addition, clinical follow-up data of patients and circulating tumor cells from liquid biopsies will be used to evaluate the role of DTCs as a biomarker of biological tumor activity.The project will be completed over a two-year period as a Postdoctoral Research Fellow at the Johns Hopkins University Hospital in Baltimore in the Laboratory of the Department of Hepatopancreatobiliary Surgery (Director Prof. C.L. Wolfgang).