The Heeren-Hagemann Lab
The Heeren Hagemann research group deals with questions concerning the development and treatment of pediatric tumors such as neuroblastoma and its metastases in the zebrafish animal model.
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Why use zebrafish for cancer research?
Zebrafish are established animal models in science since the 60s. They develop cancer spontaneously that is histologically and genetically comparable to human cancers. The first transgenic cancer model for acute lymphoblastic leukemia (ALL) in zebrafish was created in 2003. Nowadays, there are many different cancer models available such as neuroblastoma or rhabdomyosarcoma models.
Zebrafish embryos are completely transparent and they develop a recognizable body-plan with heartbeat and muscle movements already during the first 24 hours of life. Adult fish can be kept space savingly as they are small (ca. 3 cm) schooling fish and one female can produce around 300 eggs per week which can even be kept in 96-well plates for bigger screens.
Establishment of a human-zebrafish xenograft platform for individual drug response prediction in acute lymphoblastic leukaemia (ALL ZeFiX)
Acute lymphoblastic leukaemia (ALL) is the most frequent cancer among children below 15 years of age with an incidence of 4 in 100,000 children in the German population per year. Well-conducted risk-stratified therapy optimisation trials have pushed survival to 80% in the last decades. However, overall survival in the 20% of ALL patients who suffer relapse drops to only 50%. One of the biggest challenges of clinical trials for oncology treatments nowadays are immediate and long-term toxic side-effects. Predicting individual response to defined drug combinations would greatly help therapy adaptation and balance the efficient eradication of cancer cells with minimising unnecessary side effects for young patients who suffer from leukaemia or other cancers.
In collaboration with PD Dr. Cornelia Eckert, head of the in house ALL-Biobank, we are about to establish a human-zebrafish xenograft platform (ALL-ZeFiX) at our science facility adjacent to the Paediatric Oncology Department of the Charité, Berlin that will provide a fast tool to predict individual patient response to a variety of treatment courses prior to application. Human cancer cells are implanted into 2-day old embryos that can then be bathed in small molecular, targeted drugs relevant for high risk patients with a response prognosis being available in one week.
In a first row of experiments, we could show the efficacy of the BCL2-inhibitor, venetoclax, to reduce proliferation of native bone marrow biopsies from patients with ALL transplanted into host fish embryos (Gauert et al., 2020). An alternative proliferation of leukaemia cells from bone marrow biopsies in vitro is difficult to date and amplification in xenograft mouse models takes too long for clinical application. Our ZeFiX assay aims to evaluate human-zebrafish xenografts for predicting individual patient response and allow necessary treatment adaptation for relapse/refractory cancer patients within one week of cell biopsy. We are presently adapting this technique to other cancer entities such as sarcoma and neuroblastoma.
These projects are presently supported by the German Cancer Consortium (DKTK) and a Lydia Rabinowitch sponsorship.
Dr. Heeren-Hagemann's publication list
Jordan JEL, Bertalan G, Meyer T, Tzschätzsch H, Gauert A, Bramè L, Herthum H, Safraou Y, Schröder L, Braun J, Hagemann AIH, Ingolf Sack. Microscopic multifrequency MR elastography for mapping viscoelasticity in zebrafish. Magn Reson Med. 2022 Mar;87(3):1435-1445.
Bei Y, Bramè L, Kirchner L, Fritsche-Günther R, Kunz S, Bhattacharya A, Köppke J, Proba J, Wittstruck N, Sidorova OA, Chamorro González R, Dorado Garcia H, Brückner L, Xu R, Giurgiu M, Rodriguez-Fos E, Koche R, Schmitt C, Schulte JH, Eggert A, Haase K, Kirwan J, Hagemann AIH, Mertins P, Dörr JR, Henssen AG. Amplicon structure creates collateral therapeutic vulnerability in cancer. bioRxiv. 2022 Sept 12.
Lazaro-Navarro J, Pimentel-Gutiérrez HJ, Gauert A, Hagemann AIH, Eisenschmid JL, Goekbuget N, Vick B, Jeremias I, Seyfried F, Meyer LH, Debatin KM, Richter K, Bultmann M, Neumann M, Haenzelmann S, Serve H, Astrahantseff K, Rieger MA, Eckert C, Baldus CD, Bastian L. Inhibiting Casein Kinase 2 Sensitizes Acute Lymphoblastic Leukemia Cells to Venetoclax Via MCL1 Degradation. Blood Adv. 2021 Oct 5.
Grunewald L, Lam T, Andersch L, Klaus A, Schwiebert S, Winkler A, Gauert A, Heeren-Hagemann AI, Astrahantseff K, Klironomos F, Thomas A, Deubzer HE, Henssen AG, Eggert A, Schulte JH, Anders K, Kloke L, Künkele A. A Reproducible Bioprinted 3D Tumor Model Serves as a Preselection Tool for CAR T Cell Therapy Optimization. Front Immunol. 2021 Jun 29.
Gauert A, Olk N, Pimentel-Gutiérrez H, Astrahantseff K, Jensen LD, Cao Y, Eggert A, Eckert C, Hagemann AI
Fast, In Vivo Model for Drug-Response Prediction in Patients with B-Cell Precursor Acute Lymphoblastic Leukemia. Cancers 2020, 12, 1883.
Brinkmann EM, Mattes B, Kumar R, Hagemann AI, Gradl D, Scholpp S, Steinbeisser H, Kaufmann LT, Ozbek S.
Secreted frizzled-related protein 2 (sFRP2) redirects non-canonical Wnt signaling from Fz7 to Ror2 during vertebrate gastrulation. J Biol Chem. 2016 Apr 29.
Stanganello E, Hagemann AI, Mattes B, Sinner C, Meyen D, Weber S, Schug A, Raz E, Scholpp S.
Filopodia-based Wnt transport during vertebrate tissue patterning. Nat Commun. 2015 Jan 5;6:5846.
Chen Q, Su Y, Wesslowski J, Hagemann AI, Ramialison M, Wittbrodt J, Scholpp S, Davidson G.
Tyrosine phosphorylation of LRP6 by Src and Fer inhibits Wnt/β-catenin signalling. EMBO Rep. 2014 Dec;15(12):1254-67.
Hagemann AI, Kurz J, Kauffeld S, Chen Q, Reeves PM, Weber S, Schindler S, Davidson G, Kirchhausen T, Scholpp S.
In vivo analysis of formation and endocytosis of the Wnt/β-catenin signaling complex in zebrafish embryos. J Cell Sci. 2014 Sep 15;127.
Hagemann AI, Scholpp S.
The Tale of the Three Brothers - Shh, Wnt, and Fgf during Development of the Thalamus. Front Neurosci. 2012 May 28;6:76.
Hagemann AI, Xu X, Nentwich O, Hyvonen M, Smith JC.
Rab5-mediated endocytosis of activin is not required for gene activation or long-range signalling in Xenopus. Development. 2009 Aug;136(16):2803-13.
Saka Y, Hagemann AI, Smith JC.
Visualizing protein interactions by bimolecular fluorescence complementation in Xenopus. Methods. 2008 Jul;45(3):192-5.
Smith JC, Hagemann AI, Saka Y, Williams PH.
Understanding how morphogens work. Philos Trans R Soc Lond B Biol Sci. 2008 Apr 12;363(1495):1387-92
Hagemann AI*, Saka Y*, Piepenburg O, Smith JC.
Nuclear accumulation of Smad complexes occurs only after the midblastula transition in Xenopus. Development. 2007 Dec;134(23):4209-18.
Epting D, Vorwerk S, Hagemann A and Meyer D.
Expression of rasgef1b in zebrafish. Gene Expr. Pattern 7 (2007), 389-395.
Williams PH, Hagemann A, González-Gaitán M, Smith JC.
Visualizing long-range movement of the morphogen Xnr2 in the Xenopus embryo. Curr Biol. 2004 Nov 9;14(21):1916-23.