Molecular biology projects
CELL and MOLECULAR BIOLOGY TEAM
Molecular mechanisms of drug resistance and metastasis development in multiple myeloma
Multiple myeloma (MM) is yet uncurable malignancy of the terminally differentiated plasma cells. Formation of metastasis and development of drug resistance belong to the main pathogenic mechanisms with limited therapeutical options. In order to better understand these processes on molecular and cellular level, we use bottom up and hypothesis-driven approaches based on deep genomic and transcriptiomic analysis of MM patient samples. Recently, we have identified several genetic and transcriptomic changes in malignant plasma cells that are directly linked to resistance to the most commonly used drugs (proteasomal inhibitors and immunomodulatory agents) in the treatment of MM. Further, we have found genes that seem to be involved in modulation of MM cells ability to migrate out of the supportive bone marrow environment and home in other tissues. To study the resposible molecular processes we use state-of-the art equipment and approaches inlcuding proteomic, biochemical, genetic, functional cell-based and in vivo (mouse models and patient derived cells) analysis. Particularly, we focus on a complex enzymatic network involved in ubiquitin-proteasome system, regulation of oxidative stress and actin cytoskeleton. The main goal of our research is to identify novel disease biomarkers, evaluate putative drug targets, and unveil yet undescribed, fundamental biological processes.
Study of oncogenic MyD88 signalling for discovery of new therapeutic targets in Waldenstom macroglobulinema and Diffuse large B cell Lymphoma
The key adaptor protein of innate immunity MyD88 and IRAK kinases orchestrate cell signalling of IL-1β, IL-18, and most toll like receptors (TLRs). Pathological mutations in MyD88 transform B cells into Waldenstrom macroglobulinemia and aggressive forms of lymphoma (ABC DLBCL) by mimicking receptor stimulation and activating prosurvival signaling pathways. However, the composition of aberrant MyD88 signalling complexes and underlying molecular processes remain unresolved. Using proteomic, genetic, and functional approaches, we interrogate the assembly and composition of MyD88 protein complexes and determine requirement for E3 ubiquitin ligases and deubiquitinases and their interplay with IRAKs and other kinases. Specifically, we probe the noncatalytic scaffolding function of IRAK1 kinase and its regulation by ubiquitination. Ultimately, we aim to identify new targets for development of potent and specific modulators for combined and stand-alone immune therapy in lymphoma and other MyD88 dependent diseases.