The Heeren-Hagemann Lab

The aim of Dr. Heeren-Hagemann and her group is to establish a human-zebrafish xenograft platform at our research facility adjacent to the Pediatric Hematology and Oncology Department at the Charité that will provide a fast tool to predict individual patient responses to a variety of drugs prior to application during treatment.

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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)

Figure 1: Individual drug testing workflow for refractory cancer patients
Figure 2: Innate immune cells of the zebrafish interfere with human graft cell expansion

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 alternative cytostatic 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.

 

This project is supported by the Berlin Cancer Foundation (Berliner Krebsgesellschaft), the German Cancer Consortium (DKTK) and the José-Carreras Leukemia Foundation.

Dr. Heeren-Hagemann's publication list

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.



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