Institute of Molecular Genetics of the Czech Academy of Sciences
Laboratory of Genome Integrity
DNA damage, cellular senescence, glioma, cancer resistance, PML
Cells with unfinished DNA damage signalling (uDDS) caused by complex or difficult to repair DNA damage (called senescent cells) secrete a diverse set of factors, including pro-inflammatory cytokines and TGF beta family morphogens with multifaceted impact on surrounding tissues. The composition of this secretome, termed senescence-associated secretory phenotype (SASP), is shaped by numerous factors including nature of DNA-damaging stimulus, cell type and metabolic state, and cell-to-cell interaction in surrounding tissues; therefore, the composition of SASP has to be studied for each specific biological condition. The importance of studying SASP to uncover the pathogenesis of human diseases comes from studies including ours demonstrating, for instance, its impact on malignant features of cancer cells such as proliferation, invasiveness and migration, cancer stem cell mobilization, and therapeutic resistance. Analyses of secretomes directly in tissues are currently technically challenging. New methods and approaches have to be developed to decipher the complex information exchange among cells in the organism and its impact on homeostasis.
Our research includes understanding the molecular mechanisms leading to uDDS, cellular responses to uDDS, including phenotypic manifestation of the altered secretory milieu in response to uDDS, and defining molecular targets to develop new therapeutic approaches.
1) Understanding the nature of complex/unrepaired DNA damage Besides telomeres, ribosomal DNA (rDNA) loci represent repetitive DNA sequences being difficult to repair. We focus on specific mechanisms damaging rDNA loci, their repair, stability and role in tumorigenesis.
2) Role of the tissue microenvironment in glioma therapeutic resistance High-grade gliomas belong to less treatable human malignant tumours. In cooperation with Karolinska Institute, Sweden, and medical faculties of Masaryk University, Brno and Palacky University, Olomouc, we seek to reveal the molecular mechanisms behind glioma therapeutic resistance.
3) Development of new drugs and nanotherapeutics In frame of the cooperation network including University Hospital of Hradec Kralove, Czech Technical University in Prague, and Second Faculty of Medicine, Charles University, Prague we are developing new compounds with anti-tumour and anti-aging properties (senolytic and senomodulatory drugs) and nanotechnology-based approaches for cancer treatment.