TRR 54:  Growth and Survival, Plasticity and Cellular Interactivity of Lymphatic Malignancies

• Subject Area: Medicine
• Term: from 2008 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 34712712

Understanding the genetic mechanisms of tumour development, progression and treatment sensitivity is the central goal of molecular cancer research. Over decades, researchers aimed to identify activated oncogenes and inactivated tumour suppressor genes to explain the specific malignant pathogeneses by the complex interplay of aberrant gene activities, and, thus, to probe such genetic lesions as potential targets for novel therapies. The Transregional Collaborative Research Centre was initiated to integrate our current knowledge into a next level of understanding that considers various cellular conditions and interdependencies with the tumour microenvironment in a "multi-dimensional" fashion.
We are particularly interested in the plasticity and the survival strategies of cancer cells as well as in their interactions with the host on one side and with each other, i.e. communications in between tumour cells of different cellular conditions, on the other side. Therefore, the Transregional Collaborative Research Centre will not only address deregulated key signalling cascades and oncogenic activities in lymphoid cell growth and survival, but seeks to dissect the phenotypic diversity of (epi-)genetically reprogrammed tumour cells, and the functional interactions of apoptotic, senescent and proliferating conditions within the tumour cell pool and with respect to its bi-directional relationship to the host.
Based on a deeper understanding of tumour biology, the Transregional Collaborative Research Centre expects to deduct conceptually novel molecular anticancer treatment strategies by utilising more physiological co-culture systems and in vivo mouse lymphoma models. The Transregional Collaborative Research Centre is particularly interested in such lymphoid entities whose pathogenesis and clinical behaviour are not explained by mere cell-autonomous alterations: classical Hodgkin's disease with its mostly non-neoplastic, inflammation-like cellular composition, multiple myeloma with its common presentation as a destructive "myeloma bone disease" and Non-Hodgkin's lymphomas whose clinical course often seems to be driven by type and extent of infiltrating immune cells in the surroundings of the malignant cells.
The Transregional Collaborative Research Centre aims to test whether - in addition to conventional cytostatic therapies and novel, targeted therapies that interfere with defined genetic lesions within the tumour cell - so called "conceptual therapies" that interfere with dysfunctional principles of the tumour and its environment may have further clinical potential.

• DFG Programme: CRC/Transregios

Completed projects

• A01 - CD30 Signaling in normal B Cell Development and Tumorigenesis (Project Heads Bornkamm, Georg Wilhelm ;  Zimber-Strobl, Ursula )
• A02 - Functional implications of selectively NF-kB/Rel- and IKK-mediated Gene Signatures in Hodgkin Lymphoma Cells and in Lymphomagenesis (Project Head Scheidereit, Claus )
• A03 - Evaluation of IKK2/ß Inhibition as targeted Therapy in B Cell Lymphomas and the Role of c-Rel Overexpression in B Cell Lymphomagenesis (Project Head Schmidt-Supprian, Marc )
• A04 - Functional Plasticity of hypermutating B Cell Lymphomas (Project Head Jungnickel, Berit )
• A05 - Functional Characterization of the SET Domain Protein BCL 12 that is deregulated in diffuse large B Cell Lymphoma by an Immunoglobulin Gene Translocation (Project Head Ruland, Jürgen )
• A06 - The Role of Differentiation Status and Plasticity of the Lymphoma-initiating Cell in Pathogenesis of large Cell anaplastic Lymphoma in a conditional NPM-ALK Model (Project Heads Duyster, Justus ;  Miething, Cornelius )
• A07 - Drug-induced Apoptosis and Senescence: Interaction with the adaptive Immune System in c-myc induced murine B Cell Lymphomas (Project Heads Bornkamm, Georg Wilhelm ;  Gerbitz, Armin ;  Schmitt, Clemens A. )
• B01 - The patho-physioligical Role of Lineage-specific Transcription Factors, PU.1 and C/EBPa, in Identity and Tumorigenesis of B lymphatic Neoplasias (Project Head Rosenbauer, Frank )
• B02 - Molecular Genetics of C/EBP mediated myeloid-lymphoid Plasticity (Project Heads Kowenz-Leutz, Elisabeth ;  Leutz, Achim ;  Scheller, Ph.D., Marina )
• B03 - Mechanisms and Consequences of ABF-1 and Id2-mediated Plasticity of the malignant Transformation of lymphoid Cells (Project Heads Dörken, Bernd ;  Janz, Martin ;  Mathas, Stephan )
• B04 - Epigenetic Components of cellular Transdifferentiation in molecular Pathogenesis of Hogdkin Lymphoma and diffuse large B Cell Lymphoma (Project Heads Hummel, Michael ;  Stein, Harald )
• B05 - The Importance of E2F6/Polycomb Complexes for Identity of normal lymphatic Cells and its Deregulation in lymphatic Neoplasias (Project Head Hagemeier, Christian )
• B06 - Functional Dissection and Targeting of aberrant Differentiation through deregulated Notch Signaling in Hodgkin Lymphoma and multiple Myeloma (Project Heads Dörken, Bernd ;  Jundt, Franziska )
• C02 - Non-Cell-autonomous Impact of Treatment-induced Senescence on Lymphoma Growth in vivo (Project Heads Lee, Soyoung ;  Schmitt, Clemens A. )
• C03 - Dissection of Stroma-derived Deregulation of Cell-Cycle Progression and Apoptosis in a Subset of CLL Cells with Progenitor Attributes (Project Heads Peschel, Christian ;  Ringshausen, Ingo )
• C04 - Niche Function of immature osteoblastic Cells for lymphatic Tumor Cells (Project Head Kieslinger, Matthias )
• C05 - The Role of Cks1 for Cell Cycle Progession, p27kip1 functionality, Tumorigenesis and Tumor Dissemination (Project Head Keller, Ulrich )
• C06 - The Role of non-malignant B Cells and immature myeloid Cells in Development and Progression of sporadic B Cell Neoplasias and solid Tumors (Project Heads Blankenstein, Thomas ;  Willimsky, Gerald )
• INF - Integrated Data Management (Project Head Leser, Ulf )
• Z01 - Administration, Coordination, Organization and scientific Integration (Project Head Dörken, Bernd )
• Z02 - Translation of Model-based Findings to primary human lymphoid Neoplasia (Project Heads Hummel, Michael ;  Stein, Harald )

• Applicant Institution: shared FU Berlin and HU Berlin through:; Charité - Universitätsmedizin Berlin
• Participating University: Ludwig-Maximilians-Universität München
• Co-Applicant Institution: Freie Universität Berlin; Humboldt-Universität zu Berlin; Technische Universität München (TUM)
• Participating Institution: Deutsches Rheuma-Forschungszentrum Berlin (DRFZ); Helmholtz Zentrum München; Deutsches Forschungszentrum für Gesundheit und Umwelt; Max-Delbrück-Centrum für Molekulare Medizin (MDC); Max-Planck-Institut für Biochemie (MPIB)
• Spokesperson: Professor Dr. Bernd Dörken