Project Details
Projekt
TRR 17: Ras-dependent Pathways in Human Cancer
Subject Area
Biology
Medicine
Medicine
Term
from 2004 to 2013
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 5486087
Cancer affects 1,600,000 people each year in Europe, resulting in approximately 900,000 deaths. An overwhelming body of work defines cancer as a disease of aberrant cell signalling. While the individual molecules that constitute signal transduction pathways, their biochemical functions and the way they are mutated in human cancers are increasingly well understood, we know very little about how deregulated signal transduction translates into those cellular and clinical phenomena that ultimately dictate the course of the disease in the patient. This is particularly true for the Ras pathway, which has emerged as a key signal transduction pathway that contributes to the genesis of a wide variety of human tumours.
The striking observation underlying much of the work in this initiative is that the outcome of deregulated signalling through the Ras pathway is not stereotype, but is dictated by the genetic status of the cell. Biologically, this is of outmost importance. Humans harbour protective mechanisms that prevent tumour induction by a single mutation of a proto-oncogene such as Ras. As a result, multiple mutations have to accumulate in a single cell before it develops into a tumour. In tissue culture, mutations in different genes therefore show strikingly "cooperative" behaviour; in more complex environments, such as in mouse models or in human patients, where the genetic status of individual tumours is usually unknown, tumour development frequently becomes unpredictable.
Therefore, we need to understand how the genetic status of a cell affects the outcome of deregulated signalling through the Ras pathway. To achieve this aim, it is required to integrate genomic technologies, including expression arraying, proteomics and functional genomic technologies with more traditional biochemical approaches. It also requires the establishment of mouse models that mimic the human disease and allow the test of specific hypotheses in an intact animal. We believe that the new funding instrument of the Transregio Collaborative Research Centre offers an instrument that can provide the necessary integration. In this Transregional Collaborative Research Centre we bring together researchers with a strong background in signal transduction and transcriptional mechanisms with clinical researchers with a background in molecular oncology.
The striking observation underlying much of the work in this initiative is that the outcome of deregulated signalling through the Ras pathway is not stereotype, but is dictated by the genetic status of the cell. Biologically, this is of outmost importance. Humans harbour protective mechanisms that prevent tumour induction by a single mutation of a proto-oncogene such as Ras. As a result, multiple mutations have to accumulate in a single cell before it develops into a tumour. In tissue culture, mutations in different genes therefore show strikingly "cooperative" behaviour; in more complex environments, such as in mouse models or in human patients, where the genetic status of individual tumours is usually unknown, tumour development frequently becomes unpredictable.
Therefore, we need to understand how the genetic status of a cell affects the outcome of deregulated signalling through the Ras pathway. To achieve this aim, it is required to integrate genomic technologies, including expression arraying, proteomics and functional genomic technologies with more traditional biochemical approaches. It also requires the establishment of mouse models that mimic the human disease and allow the test of specific hypotheses in an intact animal. We believe that the new funding instrument of the Transregio Collaborative Research Centre offers an instrument that can provide the necessary integration. In this Transregional Collaborative Research Centre we bring together researchers with a strong background in signal transduction and transcriptional mechanisms with clinical researchers with a background in molecular oncology.
DFG Programme
CRC/Transregios
International Connection
Denmark
Completed projects
- A01 - Role of 3pK and Bmi-1 as nuclear effectos of the oncogenic Ras/Raf/MEK/ERK signalling cascade (Project Head Rapp, Ulf Rüdiger )
- A02 - Role of FoxO proteins in oncogene co-operation (Project Head Eilers, Martin )
- A03 - Regulation and function of PPARbeta/gamma in tumor stroma cells (Project Head Müller, Rolf )
- A04 - Plasticity of cell migration through oncogenic transformation (Project Head Friedl, Peter )
- A05 - In vitro and in vivo cooperation between oncogenic K-Ras and NFATc1 in pancreatic carcinogenesis (Project Head Ellenrieder, Volker )
- A06 - Oncogene-induced senescence in melanocytes (Project Head Meierjohann, Svenja )
- A07 - CXorf22 in integrin-dependent tumor invasion (Project Head Grosse, Robert )
- B01 - Crosstalk of the retinoblastoma and Ras pathways (Project Head Gaubatz, Stefan )
- B02 - Role of p53 core domain interactions for target gene selection and tumor suppression (Project Head Stiewe, Thorsten )
- B03 - Modulation of p73 expression by cell density and Ras activity (Project Head Dobbelstein, Matthias )
- B04 - Identification and characterization of tumor modifier genes for malignant melanoma (Project Head Schartl, Ph.D., Manfred )
- B05 - Role of the Myc/Miz1 interaction in the co-operation of Ras and Myc (Project Heads Eilers, Martin ; Elsässer, Hans-Peter ; Wanzel, Michael )
- B06 - Crosstalk of Ras/Raf and TGF-ß signaling (Project Head Knaus, Petra )
- B07 - Lung Cancer Susceptibility Genes - Modulation of Ras/Raf Oncogenicity by Bag-1 and Myc (Project Heads Götz, Rudolf ; Rapp, Ulf Rüdiger )
- B08 - Biochemical characterisation of LINC complexes (Project Heads Brehm, Alexander ; Sickmann, Albert )
- C02 - Interference of ICSBP deficiency with p53 function in the regulation of BCR/ABL induced transformation and kinase inhibitor resistance (Project Head Burchert, Andreas )
- C03 - Cooperation of Ras induced signaling and the nuclear oncogene Ski in acute myeloid leukemia (AML) and malignant melanoma (Project Heads Bauer, Uta-Maria ; Neubauer, Andreas )
- C04 - Growth regulation of small cell lung cancer cells by neuropeptides (Project Heads Aigner, Achim ; Gudermann, Thomas )
- C05 - Oncogene co-operation of Ras and YB-1 in multiple myeloma (Project Head Bargou, Ralf C. )
- C06 - Regulation of N-Myc protein stability in neuroblastoma (Project Head Berwanger, Bernd )
- MGKZ05 - Ras-dependent pathways in human cancer (Project Heads Gaubatz, Stefan ; Stiewe, Thorsten )
- N01 - The Role of high molecular weight complex formation in the leukemogenic potential of leukemia-associated fusion proteins (Project Head Puccetti, Elena )
- Z01 - Gene Expression Profiling and Functional Genomics (Project Head Krause, Michael )
- Z02 - Generation of genetiacally modified mice (Project Head Rapp, Ulf Rüdiger )
- Z03 - Administration of the Transregio and Coordination of Activities (Project Heads Eilers, Martin ; Schartl, Ph.D., Manfred )
- Z04 - Tissue-based pathological analyses (Project Head Moll, Roland )
- Z07 - Gene expression profiling and functional genomics (Project Heads Ade, Carsten Patrick ; Wanzel, Michael )
Applicant Institution
Julius-Maximilians-Universität Würzburg
Co-Applicant Institution
Philipps-Universität Marburg
Spokesperson
Professor Dr. Martin Eilers
