Fischer, Matthias - A 04
Elucidating the mechanisms of spontaneous regression and differentiation in neuroblastoma using genetically engineered mouse models
Prof. Dr. Matthias Fischer
Department of Exp. Pediatric Oncology | Clinic of Pediatric and Adolescent Medicine
CMMC - PI - A 04
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Department of Exp. Pediatric Oncology | Clinic of Pediatric and Adolescent Medicine
Kerpener Str. 62
50937 Cologne
Introduction
Neuroblastoma is a pediatric tumor with a broad spectrum of clinical phenotypes, ranging from fatal progression to spontaneous regression or differentiation into benign ganglioneuroma. We previously discovered that telomere maintenance is the key hallmark of high-risk neuroblastoma, mostly conferred by induction of telomerase. While these data strongly suggest that telomere maintenance is the key molecular switch required to drive neuroblastoma to the fully malignant state, experimental models to test this hypothesis have been lacking to date.
We have recently generated constitutive Tert knock-out and Tert wild-type mouse models that precisely phenocopy the divergent disease courses of neuroblastoma. These models provide a unique opportunity to study the molecular mechanisms of progression, spontaneous regression, and differentiation. In the proposed project, we are aiming at in-depth characterization of the cellular and molecular changes that occur in Tert knock-out and Tert wild-type neuroblastomas over time. Characteristics of murine tumors will be compared with those of human neuroblastomas to validate the clinical significance of molecular processes identified in mouse models. In addition, we will use a conditional Tert knock-out model to track the fate of malignant cells over the course of differentiation towards ganglioneuroma. The conditional Tert knock-out model will also be used to investigate whether inactivation of telomerase by Cre-recombination in overt neuroblastomas alleviates the course of disease in a similar fashion as in constitutive Tert knock-out mice.
Clinical Relevance
The molecular mechanisms of spontaneous regression and differentiation in neuroblastoma are still poorly understood. We here aim to gain insights into these processes using unique mouse models that phenocopy neuroblastoma progression and regression. A detailed understanding of the mechanisms that drive these divergent phenotypes will contribute to elucidate the principles of malignant transformation and provide essential information on the utility of telomerase as a therapeutic target in cancer.
Lab Website
For more information, please check Prof. Fischer´s research website.
Affiliations
Publications generated during 1/2023-12/2025 with CMMC affiliation
2024
- Chen Z, Inague A, Kaushal K, Fazeli G, Schilling D, Xavier da Silva TN, Dos Santos AF, Cheytan T, Freitas FP, Yildiz U, Viviani LG, Lima RS, Pinz MP, Medeiros I, Iijima TS, Alegria TGP, Pereira da Silva R, Diniz LR, Weinzweig S, Klein-Seetharaman J, Trumpp A, Mañas A, Hondal R, Bartenhagen C, Fischer M, Shimada BK, Seale LA, Chillon TS, Fabiano M, Schomburg L, Schweizer U, Netto LE, Meotti FC, Dick TP, Alborzinia H, Miyamoto S, Friedmann Angeli JP. PRDX6 contributes to selenocysteine metabolism and ferroptosis resistance. Mol Cell. 2024 Dec 5;84(23):4645-4659.e9. doi: 10.1016/j.molcel.2024.10.027. Epub 2024 Nov 14. PMID: 39547224.
- Hollander JF, Szymansky A, Wünschel J, Astrahantseff K, Rosswog C, Thorwarth A, Thole-Kliesch TM, Chamorro González R, Hundsdörfer P, Hauptmann K, Schmelz K, Gürgen D, Rogasch JMM, Henssen AG, Fischer M, Schulte JH, Eckert C, Eggert A, Lodrini M, Deubzer HE. Serially Quantifying TERT Rearrangement Breakpoints in ctDNA Enables Minimal Residual Disease Monitoring in Patients with Neuroblastoma. Cancer Res Commun. 2025 Jan 1;5(1):167-177. doi: 10.1158/2767-9764.CRC-24-0569. PMID: 39760332; PMCID: PMC11774142.
- Thombare K, Vaid R, Pucci P, Ihrmark Lundberg K, Ayyalusamy R, Baig MH, Mendez A, Burgos-Panadero R, Höppner S, Bartenhagen C, Sjövall D, Rehan AA, Dattatraya Nale S, Djos A, Martinsson T, Jaako P, Dong JJ, Kogner P, Johnsen JI, Fischer M, Turner SD, Mondal T. METTL3/MYCN cooperation drives neural crest differentiation and provides therapeutic vulnerability in neuroblastoma. EMBO J. 2024 Dec;43(24):6310-6335. doi: 10.1038/s44318-024-00299-8. Epub 2024 Nov 11. PMID: 39528654; PMCID: PMC11649786.
- Vaid R, Thombare K, Mendez A, Burgos-Panadero R, Djos A, Jachimowicz D, Lundberg KI, Bartenhagen C, Kumar N, Tummler C, Sihlbom C, Fransson S, Johnsen JI, Kogner P, Martinsson T, Fischer M, and Mondal T (2024). METTL3 drives telomere targeting of TERRA lncRNA through m6A-dependent R-loop formation: a therapeutic target for ALT-positive neuroblastoma. Nucleic Acids Res52, 2648-2671. doi:10.1093/nar/gkad1242.
- Werr L, Bartenhagen C, Rosswog C, Cartolano M, Voegele C, Sexton-Oates A, Di Genova A, Ernst A, Kahlert Y, Hemstedt N, Höppner S, Mansuet Lupo A, Pelosi G, Brcic L, Papotti M, George J, Bosco G, Quaas A, Tang LH, Robzyk K, Kadota K, Roh MS, Fanaroff RE, Falcon CJ, Büttner R, Lantuejoul S, Rekhtman N, Rudin CM, Travis WD, Alcala N, Fernandez-Cuesta L, Foll M, Peifer M, Thomas RK, Fischer M; Lung NEN Network. TERT Expression and Clinical Outcome in Pulmonary Carcinoids. J Clin Oncol. 2025 Jan 10;43(2):214-225. doi: 10.1200/JCO.23.02708. Epub 2024 Sep 30. PMID: 39348606; PMCID: PMC11709002.
2023
- Alborzinia H, Chen Z, Yildiz U, Freitas FP, Vogel FCE, Varga JP, Batani J, Bartenhagen C, Schmitz W, Buchel G, Michalke B, Zheng J, Meierjohann S, Girardi E, Espinet E, Florez AF, Dos Santos AF, Aroua N, Cheytan T, Haenlin J, Schlicker L, Xavier da Silva TN, Przybylla A, Zeisberger P, Superti-Furga G, Eilers M, Conrad M, Fabiano M, Schweizer U, Fischer M, Schulze A, Trumpp A, and Friedmann Angeli JP (2023). LRP8-mediated selenocysteine uptake is a targetable vulnerability in MYCN-amplified neuroblastoma. EMBO Mol Med 15, e18014. doi:10.15252/emmm.202318014.
- Decaesteker B, Louwagie A, Loontiens S, De Vloed F, Bekaert SL, Roels J, Vanhauwaert S, De Brouwer S, Sanders E, Berezovskaya A, Denecker G, D'Haene E, Van Haver S, Van Loocke W, Van Dorpe J, Creytens D, Van Roy N, Pieters T, Van Neste C, Fischer M, Van Vlierberghe P, Roberts SS, Schulte J, Ek S, Versteeg R, Koster J, van Nes J, Zimmerman M, De Preter K, and Speleman F (2023). SOX11 regulates SWI/SNF complex components as member of the adrenergic neuroblastoma core regulatory circuitry. Nat Commun 14, 1267. doi:10.1038/s41467-023-36735-2.
- Malchers F, Nogova L, van Attekum MH, Maas L, Bragelmann J, Bartenhagen C, Girard L, Bosco G, Dahmen I, Michels S, Weeden CE, Scheel AH, Meder L, Golfmann K, Schuldt P, Siemanowski J, Rehker J, Merkelbach-Bruse S, Menon R, Gautschi O, Heuckmann JM, Brambilla E, Asselin-Labat ML, Persigehl T, Minna JD, Walczak H, Ullrich RT, Fischer M, Reinhardt HC, Wolf J, Buttner R, Peifer M, George J, and Thomas RK (2023). Somatic rearrangements causing oncogenic ectodomain deletions of FGFR1 in squamous cell lung cancer. J Clin Invest 133. doi:10.1172/JCI170217.
- Rosswog C, Fassunke J, Ernst A, Schomig-Markiefka B, Merkelbach-Bruse S, Bartenhagen C, Cartolano M, Ackermann S, Theissen J, Blattner-Johnson M, Jones B, Schramm K, Altmuller J, Nurnberg P, Ortmann M, Berthold F, Peifer M, Buttner R, Westermann F, Schulte JH, Simon T, Hero B, and Fischer M (2023). Genomic ALK alterations in primary and relapsed neuroblastoma. Br J Cancer 128, 1559-1571. doi:10.1038/s41416-023-02208-y.