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Projekt
Funktionelle Charakterisierung von Knochenmetastasen-initiierende und strahlenresistente Zellen im Prostatakarzinom
Antragstellerinnen / Antragsteller
Professor Dr. Michael Baumann; Professorin Dr. Anna Dubrovska; Professorin Dr. Mechthild Krause; Dr. Claudia Peitzsch
Fachliche Zuordnung
Hämatologie, Onkologie
Nuklearmedizin, Strahlentherapie, Strahlenbiologie
Pathologie
Reproduktionsmedizin, Urologie
Nuklearmedizin, Strahlentherapie, Strahlenbiologie
Pathologie
Reproduktionsmedizin, Urologie
Förderung
Förderung von 2018 bis 2023
Projektkennung
Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 401326337
The first objective of this study is investigation of the signaling pathways mediated by the C-X-C chemokine receptor type 4 (CXCR4), Aldehyde dehydrogenase and mannose receptor C type 2 (MRC2) - which are activated in the radioresistant prostate cancer cells and play an important role in the development of bone metastases from prostate cancer (12-14). Our previous data and studies from other group showed that CXCR4, ALDH1A1 and MRC2 positive cells are relatively radioresistant (Peitzsch, unpublished), CXCR4 and ALDH1A1 cells are highly tumorigenic and have a high migratory potential in vitro (14), and importantly, CXCR4, ALDH1A1 and MRC2 are potential markers for metastatic prostate cancer (12-14) playing a role in the tumor cell interaction with bone microenvironment (12, 14, 16, 17). The second objective of this study is an unbiased and systematic analysis of genomic and transcriptomic profiling of prostate tumor cells representing different levels of metastatic processes (primary tumors, CTC and DTC from prostate cancer patients with and without bone metastases, isogenic metastatic prostate cancer cell lines with different levels of radiosensitivity) to validate activation of CSC related signaling pathways and to understand the role of bone microenvironment in the maintenance and propagation of PCa cells with metastasis-initiating and radioresistant features. These mechanisms and phenotypes will be validated by using CRISPR/Cas9 mediated knockout of candidate genes, PCa metastatic and PDX mice models, monitoring of bone turnover in vivo, and correlation of candidate genes to clinical data and patients’ response to therapy. Thus, the aim of this project is to identify the phenotypes and mechanisms which are regulating bone metastasis initiating cells and their survival after radiotherapy, and are associated with bone microenvironment
DFG-Verfahren
Schwerpunktprogramme
