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

分析播散性肿瘤细胞以表征可手术切除的胰腺癌患者的微小残留病

• 批准号: 442599387
• 负责人: Dr. Benedict Kinny-Köster
• 金额: --
• 依托单位: School of Medicine
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/442599387?language=en
• 关键词: Analysis; disseminated; tumor; cells; characterize

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).

胰腺导管腺癌是胰腺癌最常见的亚型，5年生存率低，约为9%。这种可怕的预后在很大程度上归因于诊断晚，侵略性和治疗抵抗。如果在局部阶段早期诊断，手术切除联合化疗是最佳治愈机会的首选治疗方案。然而，具有高度转移到远处器官倾向的肿瘤的特定生物学特征是限制预后的步骤。即使在完全无边缘切除肿瘤后，约75%的患者在两年内复发（最常见于肝脏）。这表明手术后遗留在体内的播散性肿瘤细胞（DTC）的全身扩散导致这些患者转移瘤生长的假设。这种术后情况被称为微小残留病。目前的研究出版物证实了胰腺癌骨髓和肝脏中存在DTC。对微小残留病的生物学特性和遗传组成的了解仍然非常有限，但对于患者的个体术后风险分层和未来靶向治疗的发展至关重要，以改善预后和生存结局。在研究奖学金期间，将在手术时采集的样本中分析骨髓和肝脏中的DTC。在鉴定肿瘤细胞后，将使用免疫细胞化学来研究所选蛋白质的表达。上皮、移行或间充质分化的标志物代表细胞触发转移生长的潜力。分析具有免疫耐受证据的表面分子（MHC I类，PD-L1）。此外，将进行分子遗传学分析，以在细胞RNA水平上绘制突变基因序列的表达图谱（下一代测序）。实验的目的是全面表征胰腺癌中的微小残留病变，以生成全身肿瘤生物学特征。此外，患者和液体活检循环肿瘤细胞的临床随访数据将用于评估DTC作为生物肿瘤活性生物标志物的作用。该项目将在巴尔的摩约翰霍普金斯大学医院肝胆胰外科实验室（主任教授C.L. Wolfgang）。

项目成果

Inflammatory Signaling and Fibroblast-Cancer Cell Interactions Transfer from a Harmonized Human Single-cell RNA Sequencing Atlas of Pancreatic Ductal Adenocarcinoma to Organoid Co-Culture

• DOI: 10.1101/2022.07.14.500096
• 发表时间: 2022-07
• 期刊: bioRxiv
• 作者: B. Kinny-Köster;Samantha Guinn;Joseph A Tandurella;Jacob T. Mitchell;Dimitri N. Sidiropoulos;Melanie Loth-Melan

Multi-omic analyses of changes in the tumor microenvironment of pancreatic adenocarcinoma following neoadjuvant treatment with anti-PD-1 therapy.

• DOI: 10.1016/j.ccell.2022.10.001
• 发表时间: 2022-11-14
• 期刊: CANCER CELL
• 影响因子: 50.3
• 作者: Li, Keyu;Tandurella, Joseph A.;Gai, Jessica;Zhu, Qingfeng;Lim, Su Jin;Thomas II, Dwayne L.;Xia, Tao;Mo, Guanglan;Mitchell, Jacob T.;Montagne, Janelle;Lyman, Melissa;Danilova, Ludmila, V;Zimmerman, Jacquelyn W.;Kinny-Koster, Benedict;Zhang, Tengyi;Chen, Linda;Blair, Alex B.;Heumann, Thatcher;Parkinson, Rose;Durham, Jennifer N.;Narang, Amol K.;Anders, Robert A.;Wolfgang, Christopher L.;Laheru, Daniel A.;He, Jin;Osipov, Arsen;Thompson, Elizabeth D.;Wang, Hao;Fertig, Elana J.;Jaffee, Elizabeth M.;Zheng, Lei
• 通讯作者: Zheng, Lei