Project Details
Projekt
Characterization of the premetastatic niche at different sites and in vivo imaging of granulocytic myeloid derived suppressor cells
Applicant
Dr. Christoph Grießinger
Subject Area
Nuclear Medicine, Radiotherapy, Radiobiology
Term
from 2013 to 2014
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 250022035
A significant hallmark of cancer is the appearance of metastasis, frequently representing the final stage of a cancer disease. It is conspicuous, that some tumor types prefere specific organs for metastatic spread. Contrary to obsolete theories, which describe metastasis formation as random event, the metastatic spread is considered nowadays as multi-step process, initiated by the formation of the premetastatic niche (PMN) in the target organ before circulating tumor cells are able to seed. As a consequence of signaling of the primary tumor, an infiltration of different bone marrow derived stem cell types, an increased expression of characteristic adhesion molecules and a remodeling of the extracellular matrix occurs. Hypoxia within the primary tumor induces signaling which results in an increased appearance of PMN, accompanied by an infiltration of granulocytic myeloid derived suppressor cells (G-MDSCs). So far, mainly the development of the PMN in the lung was described in recent publications. In this project the appearance of PMN in the bone marrow and brain will be investigated in a murine breast cancer-metastasismodel (PymT). Specially generated Cherry-red/Luciferase-transgenic-PymT-breastcancer cells with specificity for metastasis in the bone marrow and brain will be used. In these experiments, the treatment of experimental animals with hypoxic conditioned medium derived from bone marrow- or brain-specific breastcancer-cells induces the increased appearance of PMN at the respective sites. This project focuses on the characterization of PMN in the bone marrow and brain, as well as the in vivo imaging of the migration of G-MDSCs to the PMN and can be divided into the following subprojects:During funding period:A) Characterization of G-MDSCs within the PMN of the bone marrow and brain.B) In vivo Optical Imaging of metastatic spread in the lung, bone marrow and brain.C) Establishment of the labeling with the fluorescence dye Cy5 for isolated G-MDSCs. After adoptive transfer, the homing of these G-MDSCs to the PMN in the lung, bone marrow and brain will be visualized by Optical Imaging. After funding period:D) Establishment of PET- (radioactive CD11b-monoclonal antibodies, herpes-simplex-thymidine-kinase-reportergene) or MRI-compatible labeling strategies (iron oxide particles, 19F) for G-MDSCs for the in vivo detection of their homing to the PMN by simultaneous PET/MRI. E) Simultaneous PET/MRI of the PMN by adoptively transferred G-MDSCs in alternative murine metastasis-models and development of PMN-specific tracers. In summary, in this project the development of the PMN in the bone marrow and brain will be investigated and subsequently the migration dynamics of G-MDSCs to PMN will be established to predict the location of the future metastasis. The proposed experiments will sustain after the funding period beyond 2015.
DFG Programme
Research Fellowships
International Connection
Australia
