Project Details
Projekt
Dissecting the role of extracellular vesicles and their miRNA cargo in prostate cancer. From expression pattern to bone metastasis phenotype.
Applicants
Dr. Stefanie Conrad; Professor Dr. Lorenz C. Hofbauer
Subject Area
Hematology, Oncology
Endocrinology, Diabetology, Metabolism
Endocrinology, Diabetology, Metabolism
Term
from 2018 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 401071709
Metastatic colonization of the skeleton is a common complication of advanced prostate cancer (PCa). PCa cells can alter the bone microenvironment even before the metastatic spread, suggesting the presence of a pre-metastatic niche. Extracellular vesicles (EVs) have emerged as crucial players in tumor initiation and progression, contributing to the establishment of a pre-metastatic niche. MicroRNAs (miRNAs) are small non-coding RNAs that may mediate some of the effects of EVs in the cancer-bone dialogue. Our previous studies indicate that PCa-EVs impair osteogenesis and bone mineralization by transferring miRNAs, thereby modifying bone formation, the inflammatory response of osteoblasts, and the phenotype of bone metastases. In this project, we hypothesize that EVs and their miRNA cargo control PCa homing to bone, impair osteoblast and osteoclast functions, and foster immune evasion. We propose that these alterations contribute to PCa progression in bone and regulate the phenotype of bone metastases. Our specific objectives are (I) to assess the effects of EVs on PCa osteotropism in vitro and in vivo, including tumor migration and associated bone cell cross-talks; (II) to decipher the effects of miR-26a-5p, miR-27a-3p, and miR-30e-5p on PCa homing to bone in murine models and human disease. This includes comprehensive analysis of these miRNAs on migration and other determinants of tumor progression as well as interactions with bone remodeling using murine models and human tissues from our BoneBank that allows a link to the skeletal phenotype (osteosclerostic/ osteolytic); (III) to define osteoimmune mechanisms how EV-derived miRNAs in PCa pre-educate the bone microenvironment. This involves a comprehensive characterization of the bone immune microenvironment in PCa with mass cytometry (CyTOF), followed by confirmation with immunohistochemistry and cytokine assays, focusing on IL-6 signaling. Results will then be validated in human material from the BoneBank. These studies actively involve a clinician-scientist. Elucidation of these processes and mechanisms in preclinical, murine models, and human disease could pave the way for targeted interference with these disease-causing mechanisms.
DFG Programme
Priority Programmes
