Project Details
Projekt
Molecular characterization and targeting of radioresistant prostate cancer stem-like cell populations with bone metastasis-initiating properties
Applicants
Professorin Dr. Anna Dubrovska; Professorin Dr. Mechthild Krause; Privatdozentin Dr. Annett Linge
Subject Area
Hematology, Oncology
Pathology
Reproductive Medicine, Urology
Pathology
Reproductive Medicine, Urology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 491692296
Metastatic tumors cause more than 90% of cancer-related deaths. Prostate cancer (PCa) bone metastases have a heterogeneous response to treatment. Current therapies for osseous metastatic disease, including radiotherapy, frequently fail to provide a durable treatment response. To date, there are only limited therapy options for metastatic PCa, the mechanisms that drive the survival of bone metastasis-initiating cells (MIC) are poorly characterized, and reliable prognostic markers are missing. During the first funding period, we characterized the prognostic potential and the heterogeneity of CTC in metastatic castration-resistant PCa (mCRPC) patients treated with ablative radiotherapy to the metastatic lesions (n = 100). We have employed different in vivo models of metastatic PCa, such as xenograft and syngeneic mice models, and xenograft zebrafish models to demonstrate that prostate tumor cell survival in blood circulation, tumor homing to bone and bone marrow colonization is positively regulated by ALDH1A1 and negatively regulated by ALDH1A3 proteins. Furthermore, immunohistochemical analysis of ALDH1A1 expression levels showed its significant upregulation in distant metastases compared to the primary tumor sites. This analysis also showed that the expression level of ALDH1A1 in primary tumors negatively correlates with disease-free survival in PCa patients. We found that β-catenin triggered ALDH1A1 transcription positively regulates cell radioresistance, tumor cell survival in the blood vessels, and extravasation. Our study showed that the opposite role of ALDH1A1 and ALDH1A3 proteins in tumor cell survival, dissemination, and bone colonization could be partially attributed to their different TGFβ and MPP gene expression regulation. We found that the β-catenin/ALDH1A1 axis is upregulated in radioresistant MIC populations and activates other genes essential for metastatic dissemination and bone colonization. To further explore the molecular characteristics and potential targeting options for radioresistant metastasis-initiating PCa cells, we plan (i) to validate the prognostic potential of CTC in PCa patients treated with radiotherapy and characterization the CTC transcriptome signature using additional patients’ cohorts; (ii) to develop a targeting strategy toward the MIC population and validating its radiosensitizing and anti-metastatic effect, and (iii) to decipher the molecular mechanisms explaining the different roles of ALDH1A1 and ALDH1A3 in the promoting expression of the metastatic-related genes, bone colonization and remodeling, and metastasis radioresistance. Our study will identify molecular signatures that select a subpopulation of patients treated with radiotherapy that are more likely to develop bone metastases. Also, our work will help elucidate the mechanisms regulating bone MIC population and identify drugs to inhibit it, and therefore, could be of high scientific and clinical value.
DFG Programme
Priority Programmes
