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

胰腺导管腺癌是胰腺癌中最常见的一种亚型，其5年生存率约为9%。这种可怕的预后在很大程度上归因于诊断较晚、侵袭性和治疗抵抗。如果在局部阶段早期诊断，手术切除联合化疗是最有可能治愈的治疗方案。然而，肿瘤的特定生物学特性是限制预后的一步，这种肿瘤有很高的转移到远处器官的倾向。即使在肿瘤完全无切缘切除后，大约75%的患者会在两年内复发(最常见的是肝脏)。这一假说表明，手术后遗留在体内的播散性肿瘤细胞(DTC)的全身扩散导致了这些患者的转移生长。这种术后状态被称为微小残留病。目前的研究文献证实，在胰腺癌的骨髓和肝脏中存在DTCs。对微小残留病的生物学特性和遗传组成的洞察仍然非常有限，但对于患者术后个体风险分层和未来靶向治疗的发展以改善预后和生存结果至关重要。在研究期间，将在手术时采集样本分析骨髓和肝脏中的DCs。在鉴定了肿瘤细胞后，将使用免疫细胞化学来研究选定的蛋白质的表达。上皮性、过渡性或间充质分化的标记物代表了细胞触发转移生长的潜力。分析有免疫耐受证据的表面分子(MHC I类，PD-L1)。此外，还将进行分子遗传分析，以在细胞的RNA水平上绘制突变基因序列的表达图(下一代测序)。实验的目的是全面描述胰腺癌的微小残留病，以产生全身肿瘤生物学的概况。此外，患者的临床随访数据和液体活检的循环肿瘤细胞将被用来评估DCs作为生物肿瘤活性生物标志物的作用。该项目将在两年内完成，他是巴尔的摩约翰·霍普金斯大学医院肝胰胆外科实验室的博士后研究员(主任C.L.沃尔夫冈教授)。

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).