Project Details
Projekt
Regulation of Tumor Cell Dormancy in Human Prostate Cancer Bone Metastasis
Applicant
Professor Tobias Lange, Ph.D.
Subject Area
Hematology, Oncology
Nuclear Medicine, Radiotherapy, Radiobiology
Nuclear Medicine, Radiotherapy, Radiobiology
Term
from 2018 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 401023770
The general aim of this project is to improve our understanding of the mechanisms that regulate outgrowth or otherwise dormancy of PCa bone metastases. This is a major clinical problem as it accounts for late metastatic relapse after unpredictable periods of minimal residual disease. Our preliminary data, which are mainly based on our newly established spontaneous bone metastasis xenograft models of human PCa, and the literature collectively suggest that the outgrowth of PCa bone metastases might be suppressed by a paracrine and/or autocrine interplay of the soluble factors Sparc and Dkk1 that apparently inhibits tumor colonization by promoting the EMT-phenotype of metastatic cells (EMT=epithelial-to-mesenchymal transition). The first aim of this project will therefore be to obtain for the first time direct functional evidence whether the bone marrow (BM) colonization changes upon genetic modification (e.g., inducible knockdown) of Sparc or Dkk1 in our spontaneous metastasis PCa xenograft models (WP1). Our preliminary work demonstrates that our models closely recapitulate the process of EMT, that they have clinical and functional relevance, and that we are able to monitor the switch from dormancy to colonization in vivo. In WP2 we will determine whether Dkk1 exerts its effects on tumor cell dormancy not only by directly targeting the tumor cells, but also the BM stromal cells. For this purpose, we will use immunodeficient mice with mutated Dkk1-binding site of the main receptor Lrp5 (Lrp5-G170V) or with knockout of the co-receptors Krm1 and/or Krm2 for cell line-based PCa xenograft experiments. In addition, we will engraft these mice with our newly established patient-derived xenograft (PDX) model 'C5' that spontaneously metastasizes to the bone and expresses Dkk1 and Sparc. WP1 and WP2 are embedded into a long-standing, close collaboration between the applicant and the Institute of Osteology and Biomechanics at UKE (Prof. Thorsten Schinke). Prof. Schinke will contribute his expertise in static, dynamic and cellular histomorphometry and provide the Lrp5-G170V and Krm1/2 k.o. mice for WP2. WP1 and WP2 might demonstrate that elevated levels of Sparc and Dkk1 and Dkk1 receptor activation suppress the switch from dormancy to colonization. The expected results would provide a rationale for future experiments on how to maintain Sparc and Dkk1 expression in the phase of minimal residual cancer to prevent metastatic relapse (presumably in a second funding period). Moreover, in order to identify novel markers of metastatic outgrowth in PCa by an unbiased approach, we will use a recently established method of bioluminescence imaging-guided in situ laser ablation of xenograft primary tumors and corresponding bone metastases and subsequent proteome analysis (WP3, cooperation with Prof. H. Schlüter, UKE). The resulting candidates will be functionally validated in a second funding period.
DFG Programme
Priority Programmes
