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Eine Mann füllt mit einer Pipette eine rote Flüssigkeit in ein kleines Glas

The Dörr Lab

The laboratory of Jan Dörr investigates the basis of tumor heterogeneity and therapy resistance in pediatric malignancies with modern molecular and cellular biology techniques in preclinical tumor models in vitro and in vivo to improve the diagnosis and therapy of pediatric cancers.

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Research of the Dörr Lab

Despite the development of targeted therapies, treatment resistance remains a critical barrier to curative cancer therapies. In addition to the occurrence of resistance mutations in tumor subpopulations, for example due to deletions of tumor suppressor genes, therapy resistance may result from differential expression of oncogenes such as RAS or MYC(N) and consequently, the manipulation of cellular failsafe mechanisms, such as apoptosis and therapy-induced senescence (TIS). The intercellular differences in oncogene dosage are predominantly caused by oncogene amplifications on extrachromosomal DNA (ecDNA), which segregates unevenly during mitosis, giving rise to cancer cells with different oncogene copy numbers. Therefore, extrachromosomal oncogene amplification gives rise to tumors with a wide range of different oncogene dosages. This intratumoral heterogeneity can spatially influence cell fate decisions after cancer therapy, such as the propensity for therapy-induced senescence (TIS) or apoptosis, and locally alter the tumor biology and the tumor environment.

TIS is induced in many malignancies in response to chemotherapy or radiotherapy due to the resulting DNA damage. The elicited DNA-damage response activates the cell-cycle regulators p21CIP1a (also known as CDKN1A) and p16INK4a (also known as CDKN2A) in a p53- and retinoblastoma protein (Rb)-dependent process. Rb recruits chromatin repressor complexes with histone methyltransferase Suv39h1-mediated H3K9 trimethylation activity to promoters of S phase genes and blocks their expression by establishing heterochromatin marks in the vicinity of their promoters. Despite their proliferation arrest TIS tumor cells undergo dynamic structural and functional changes: They alter their morphology and organelle composition, adjust their metabolism and develop a characteristic senescence-associated secretory profile (SASP). Accordingly, their reprogrammed physiology strongly impacts on tumor biology and the tumor microenvironment. In particular, senescent cells display an increased stemness potential, reprogram their metabolism and promote tumor inflammation primarily through their SASP. Therefore, senescence has been associated with both beneficial and detrimental effects on treatment outcome.

In our group scientists and physicians work together to investigate how intratumoral differences in oncogene dosage alter tumor physiology and thus contribute to treatment resistance, and whether resulting changes in tumor cell physiology offer new therapeutic opportunities for the treatment of resistant tumors, particularly with senescence-targeting therapies. Pediatric tumors are ideal model diseases to study the clinical relevance of senescence and to evaluate the potential of senescence-specific therapies. Firstly, pediatric neoplasms carry significantly fewer somatic mutations than adult tumors. Therefore, critical tumor suppressor genes, such as p53, often remain intact, which preserves the activity of cellular failsafe mechanisms, such as TIS. Secondly, neoadjuvant therapies are frequently used in pediatric oncology, so that tumor material is acquired before and after therapy in diagnostic biopsies and tumor resections respectively.

Therefore, translational research projects will investigate the clinical relevance of ecDNA-mediated, therapy-induced tumor heterogeneity and therapy resistance with a special focus on TIS using tumor mouse models, patient-derived xenografts (PDX) and tumor samples from pediatric patients with both histopathological and modern high-throughput methods (transcriptomics, proteomics, metabolomics). On this basis, minimally invasive diagnostic tools for the detection of TIS, e.g. from liquid biopsies, will be developed for different malignancies with the aim to determine the impact of TIS on treatment response and overall survival in the clinic.

Here you find more detailed information about the individual research projects in the Dörr group.

The most important publications of the Dörr Lab

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Schleich, K, Kase J, Dörr JR, et al., Mouse modeling of H3K9me3 governed senescence predicts lymphoma patient outcome. Nat. Commun., 2020; 11,3651

Milanovic M, Fan DNY, Belenki D, Dabritz JHM, Zhao Z, Yu Y, Dörr JR et al., Senescence-associated reprogramming promotes cancer stemness. Nature,2018; 553, 96

Dabritz, JHM, Yu Y, Milanovic M, Schonlein M, Rosenfeldt M, Dörr JR et al.,CD20-Targeting Immunotherapy Promotes Cellular Senescence in B-Cell Lymphoma. Mol Cancer Ther., 2016; 15, 1074

Dörr JR, Yu Y, Milanovic M, Beuster G et al., Synthetic lethal metabolic targeting of cellular senecence in cancer therapy. Nature, 2013; 501, 421

Jing H, Kase J, Dörr JR, Milanovic M, Lenze D et al., Opposing roles of NF-κB in anti-cancer treatment outcome unveiled by cross-species investigations. Genes Dev., 2011; 25, 2137

Reimann M, Lee S, Loddenkemper C, Dörr JR, Tabor V et al., Tumor stroma derived TGF-beta limits myc-driven lymphomagenesis via Suv39h1-dependent senescence. Cancer Cell, 2010; 17, 262

Cooperation partners

  • Prof. Anton Henssen (ECRC, Charité Campus Buch und MDC Campus-Buch): Untersuchung von ecDNA und Seneszenz in Neuroblastomzelllinien und PDX Modellen (in Kooperation mit EPO GmbH)
  • Prof. Johannes Schulte (Klinik für Pädiatrie m.S. Onkologie und Hämatologie, Charité): Untersuchung von Seneszenz in transgenen Neuroblastom Mausmodellen
  • Prof. Clemens Schmitt (Molekulares Krebsforschungszentrum, Medizinische Klinik für Hämatologie, Onkologie und Tumorimmunologie, Charité): Untersuchung von Seneszenz in aggressiven B-Zell Lymphomen
  • Prof. Roland Kappler (Kinderchirurgische Forschungslaboratorien, Dr. von Haunerschen Kinderspital der Ludwig-Maximilians-Universität, München): Untersuchung von Seneszenz in Hepatoblastom Zelllinien und Analyse von klinischen Hepatoblastomdatensätzen.
  • Prof. Diego Calvisi (Institut für Pathologie, Universität Regensburg): Etablierung von präklinischen Hepatoblastommausmodellen durch hydrodynamische Schwanzveneninjektion (hydrodynamic tail vein injection, HDTVI)
  • Dr. Carolina Armengol, Childhood Liver Oncology Group, Germans Trias i Pujol Research Institute, Badalona, Spanien): Analyse von Tumorgewebeproben von Hepatoblastompatienten*innen, um den Beitrag von Seneszenz zum Therapieerfolg in Hepatoblastomen zu evaluieren.
  • Dr. Stefano Cairo (Xentech, Evry-Courcouronnes, Frankreich): Bereitstellung von PDX Modellen aus Hepatoblastomen.
  • Dr. Fabian Coscia (MDC Campus Buch): Untersuchung von Tumorheterogenität durch hochauflösende, räumliche Proteomik in Zellkultur- und PDX-Modellen und Tumorgewebeproben.
  • Dr. Jennifer Kirwan (Berlin Institute of Health, Metabolomics Unit und Imaging Mass Spectrometry Unit): Analyse von metabolischen Veränderungen seneszenter Zellen in Zelllinien, PDX-Modellen und Tumorgewebeproben.
  • Dr. Mathias Rosenfeldt (Pathologisches Institut der Universität Würzburg): Histopathologische Untersuchung von Seneszenz in Tumorgewebeproben von Patienten*innen mit embryonalen Tumoren.
  • Dr. Anna Obenauf (Institut für Molekulare Pathologie, Wien, Österreich): Bereitstellung von genetischen Werkzeugen (CaTCH Technologie) zur CRISPRa-basierten Isolierung von Einzelzellen in heterogenen Zellpopulationen.
  • Prof. Maria Hondele (Biozentrum, Universität Basel, Schweiz): Analyse von membranlosen Organellen als Zielstruktur für Seneszenz-spezifische Diagnostik und Therapien in embryonalen Tumoren.

The Dörr group is currently funded within these projects:

Impact of senescence on hepatoblastoma development and therapy Deutsche Kinderkrebsstiftung

Funding from 2022-2024
Development of senescence-targeting T-cell immunotherapies for aggressive B-cell lymphomas Deutsche José Carreras Leukämie-Stiftung
Funding from 2022-2023
The impact of MYCN on therapy induced senescence in neuroblastoma Berliner Krebsgesellschaft

Funding from 2021 - 2023
Targeting membraneless organelles in therapy-induced senescence of pediatric cancers Wilhelm Sander Foundation

Funding from 2022-2024