Molecular mechanisms of irradiation-induced cellular plasticity for the development of novel biomarkers towards individualized radiotherapy
Projekt leaders:
Dr. rer. nat. Ali Nowrouzi (DKFZ, HIRO, Universitätsklinik Heidelberg), a.nowrouzi[at]dkfz.de, Phone: +49-6221-56-34638
Dr. rer. nat. Ina Kurth (DKFZ, Heidelberg), ina.kurth[at]dkfz.de, Phone: +49-6221-1665
Dr. rer. nat. Claudia Peitzsch (NCT/OncoRay, Dresden), claudia.peitzsch[at]uniklinikum-dresden.de, Phone: +49 351 458-7623
Funded since: November 2017
The proposed NCRO joint funding project aims to unravel molecular and cellular mechanisms of irradiation (IR)-induced cellular plasticity and their relation to radiotherapy failure in prostate and head and neck cancer. We hypothesize that IR-induced bidirectional conversion from non-cancer stem cells (CSCs) into CSCs may promote therapy resistance and treatment failure. Previously we have provided evidence that ionizing radiation increases the fraction of cells with CSC-like properties (Peitzsch et al; Kurth et al). From genome-wide functional genomic screens in vivo we have identified loss-of-function and gain-of-function mutations composing local recurrences following radiation therapy (Nowrouzi et al). High-resolution clonal tracing of tumour cells is providing comprehensive insights in the clonal evolution and dynamics within irradiated tumours (Nowrouzi et al). With these established platforms we seek to investigate whether the radiation-induced bidirectional conversion from non-CSCs into CSCs is a stochastic or deterministic process. We are aiming to identify molecular processes influencing radiation-induced plasticity and phenotypic switching. Therefore, cell-based and translational animal models will be applied in combination with clonal barcoding and functional genomic approaches (CRISPR, RNAi) to analyse clonal dynamics. These platforms will be combined with single cell omics (DEParray, 10xGenomics) to comprehensively understand the molecular drivers of tumour cell plasticity on the single cell level. Our findings will be validated within patient cohorts to investigate the clinical impact of these newly identified molecular processes and their potential to be used as biomarkers to improve the outcome of cancer patients with individualized radiation therapy.
The main objectives are:
- Analysis of clonal dynamics associated with IR-induced plasticity using color-coded cell populations and lentiviral based high-throughput genetic barcoding
- Identification of biological mechanisms which promote or repress IR-induced plasticity with genome-wide functional screens and single cell OMICS
- Integrative analyses of clinical datasets to validate the predictive potential of the identified biomarker for radiotherapy outcome
© DKFZ: Nowrouzi, Kurth; Oncoray: Peitzsch
Project-related references:
Cojoc, M. et al. Aldehyde Dehydrogenase Is Regulated by beta-Catenin/TCF and Promotes Radioresistance in Prostate Cancer Progenitor Cells. Cancer Res 75, 1482-94 (2015).
Kurth, I. et al. Cancer stem cell related markers of radioresistance in head and neck squamous cell carcinoma. Oncotarget 6, 34494-509 (2015).
Peitzsch, C. et al. An Epigenetic Reprogramming Strategy to Resensitize Radioresistant Prostate Cancer Cells. Cancer Res 76, 2637-51 (2016).
Nowrouzi, A. et al. The fetal mouse is a sensitive genotoxicity model that exposes lentiviral-associated mutagenesis resulting in liver oncogenesis. Mol Ther 21, 324-37 (2013).
Boztug, K. et al. Stem-cell gene therapy for the Wiskott-Aldrich syndrome. N Engl J Med 363, 1918-27 (2010).
