AG Braun: Tumor heterogeneity and treatment response in pancreatic cancer

Lena Anthuber, doctoral candidate
Kira Bichmann, doctoral candidate
Benedikt Färber, doctoral candidate
Benjamin Heckelmann, doctoral candidate
Jessica Watzelt, doctoral candidate

Our group focuses on preclinical models of pancreatic cancer to test therapy response ex vivo and facilitate personalized patient treatment. Underlying molecular mechanisms of treatment resistance in pancreatic cancer are poorly understood. There has been emerging evidence over the last few years that intratumoral heterogeneity (ITH) is a key determinant in tumor biology, treatment response and ultimately patient survival.

We aim to establish clone-specific transcriptomic and proteomic profiles associated with distinct treatment response using patient-derived primary cell lines/ organoids as well as classical cell line models.

Our group also focuses on organotypic slice cultures (OTSCs) as preclinical ex vivo model for the development of personalized treatment strategies. Most currently used preclinical models such as patient-derived cell lines/ organoids and xenografts lack the specific tumor microenvironment and therefore allow only limited response prediction. OTSCs of fresh tumor samples are a close approximation of the tumor in situ. They maintain their baseline morphology, proliferative activity and microenvironment during the cultivation for a defined, tissue-dependent period. This technique enables the immediate application of treatment to viable human tumor tissue ex vivo and subsequent downstream analyses, such as profiling of the transcriptome and proteome.

Dr. Matthias Brandenburger, Fraunhofer Research and Development Center for Marine and Cellular Biotechnology, Lübeck
PD Dr. Peter Bronsert, Institute for Pathology, University of Freiburg, Freiburg
Dr. Daniela Hirsch, Institute of Pathology, University Medical Center Mannheim, Mannheim
Prof. Dr. Thomas Ried, National Cancer Institute, Bethesda, MD, USA
Prof. Dr. Oliver Schilling, Institute for Surgical Pathology, University of Freiburg, Freiburg

Clinician Scientist School Lübeck (DFG #413535489)
Junior Funding Program of the University of Lübeck
Werner und Klara Kreitz Stiftung

Braun R, Lapshyna O, Eckelmann S, Honselmann K, Bolm L, ten Winkel M, Deichmann S, Schilling O, Kruse C, Keck T, Wellner U, Bronsert P, Brandenburger M. Organotypic slice cultures as preclinical models of tumor microenvironment in primary pancreatic cancer and metastasis. J Vis Exp. accepted manuscript

Braun R, Anthuber LM, Wangsa D, Lack J, McNeil NE, Heselmeyer-Haddad K, Torres I, Wangsa D, Brown M, Hirsch D, Tubbs A, Auslander N, Brauer PR, Cam M, Sackett DL, Habermann JK, Nussenzweig A, Ruppin E, Zhang Z, Rosenberg DW, Ried T. Single cell-derived primary rectal carcinoma cell lines reflect intratumor heterogeneity associated with treatment response. Clin Cancer Res. 2020; 26(13):3468-3480

Wangsa D*, Braun R*, Stuelten CH, Brown M, Bauer KM, Emons G, Weston LA, Hu Y, Yang HH, Vila-Casadesús M, Lee MP, Brauer P, Warner L, Upender M, Hummon AB, Camps J, Ried T. Induced Chromosomal Aneuploidy Results in Global and Consistent Deregulation of the Transcriptome of Cancer Cells. Neoplasia 2019, 21(7): 721-729, *authors contributed equally

Braun R*, Ronquist S*, Wangsa D, Chen H, Anthuber L, Gemoll T, Wangsa D, Koparde V, Hunn C, Habermann JK, Heselmeyer-Haddad K, Rajapakse I, Ried T. Single chromosome aneuploidy induces genome-wide perturbation of nuclear organization and gene expression. Neoplasia 2019, 21(4): 401-412, *authors contributed equally

Wangsa D, Braun R, Schiefer M, Gertz EM, Bronder D, Quintanilla I, Padilla-Nash HM, Torres I, Hunn C, Warner L, Buishand FO, Hu Y, Hirsch D, Gaiser T, Camps J, Schwartz R, Schäffer AA, Heselmeyer-Haddad K, Ried T. The Evolution of Single Cell-derived Colorectal Cancer Cell Lines is Dominated by the Continued Selection of Tumor Specific Genomic Imbalances, Despite Random Chromosomal Instability. Carcinogenesis 2018, 39(8): 993-1005

Yuan D, Huang S, Berger E, Liu L, Gross N, Heinzmann F, Ringelhan M, Connor TO, Stadler M, Meister M, Weber J, Öllinger R, Simonavicius N, Reisinger F, Hartmann D, Meyer R, Reich M, Seehawer M, Leone V, Höchst B, Wohlleber D, Jörs S, Prinz M, Spalding D, Protzer U, Luedde T, Terracciano L, Matter M, Longerich T, Knolle P, Ried T, Keitel V, Geisler F, Unger K, Cinnamon E, Pikarsky E, Hüser N, Davis RJ, Tschaharganeh DF, Rad R, Weber A, Zender L, Haller D, Heikenwalder M. Kupffer-cell derived TNF triggers cholangiocellular tumorigenesis through JNK due to chronic mitochondrial dysfunction and ROS. Cancer Cell 2017, 31(6):771-789 (birth name of Braun R: Meyer R)