Project Details
Projekt
Functional characterization of bone metastasis-initiating and radioresistant prostate tumor cells
Applicants
Professor Dr. Michael Baumann; Professorin Dr. Anna Dubrovska; Professorin Dr. Mechthild Krause; Dr. Claudia Peitzsch
Subject Area
Hematology, Oncology
Nuclear Medicine, Radiotherapy, Radiobiology
Pathology
Reproductive Medicine, Urology
Nuclear Medicine, Radiotherapy, Radiobiology
Pathology
Reproductive Medicine, Urology
Term
from 2018 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 401326337
Once prostate tumor spreads to the bone, it typically cannot be cured. The supportive sites in bone maintain survival and proliferation of cancer cells by special molecular components such as C-X-C motif chemokine ligand 12 (CXCL12) which also mediates tumor cell homing to bone. In turn, metastatic PCa cells in bone express different proteins that regulate both, bone remodeling and tumorigenesis including Endo 180 collagen receptor. Prostate tumors have a hierarchical organization where cancer stem cells (CSC) maintain and propagate the tumor mass. A number of studies showed a high radioresistance of CSCs compared to the tumor bulk, and many recent clinical studies use CSC related biomarkers for prediction of radiotherapy outcome. Tumor metastases are driven by the evolved populations of CSC at their worst. In support of this, cells representing different levels of metastatic processes including circulating tumor cells (CTC) in the blood of cancer patients and disseminated tumor cells (DTC) in their bone marrow express CSC markers, and metastasis initiating cells are sharing key CSC features including ability to form tumors and to activate CSC specific signaling mechanisms. Our studies revealed a few proteins that are involved in regulation of metastatic and radioresistant prostate tumor cells. That includes aldehyde dehydrogenase protein 1A1 (ALDH1A1) which is a marker of radioresistant CSC and has a high expression in PCa metastases. Another example is CXCL12 receptor, CXCR4, which is a marker of CSC, upregulates in CTC after radiotherapy and correlates with radiotherapy outcome in PCa. Finally, expression of collagen receptor Endo180/MRC2 which is one of the key regulators of PCa metastases is upregulated in highly tumorigenic radioresistant PCa cells. We assume that activation of certain signaling pathways detected on the genomic and transcriptomic levels in bone-marrow DTC, CTC or CSC in primary tumors can be prognostic for bone metastasis development and, on other hand, can be involved in the bone remodeling and response of metastases to radiotherapy. The first objective of this study is investigation of the role of signaling pathways mediated by CXCR4, ALDH1A1 and Endo180 for regulation of bone metastasis-initiating and radioresistant prostate tumor cells and bone remodeling, and possible interaction of these mechanisms during metastatic development. 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, CSC, CTC, DTC, radioresistant PCa cells) to validate activation of CSC related signaling pathways. These mechanisms and phenotypes will be validated by using CRISPR/Cas9 mediated knockout of candidate genes, metastatic mice models, monitoring of bone remodeling in vitro and in vivo, and correlation of candidate genes to clinical data and patients’ response to therapy.
DFG Programme
Priority Programmes
