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Mitosis and Drug Discovery

Aims in short

The Mitosis and Drug Discovery Team of VTT investigates mechanisms of cell division in somatic cells and in meiotic systems. Understanding cell division errors may help to explain origin of genomic instability and is expected to identify novel therapeutic possibilities for treatment of cancer. We are also performing high-throughput screens (HTS) for small molecules, siRNAs and miRNAs with anti-mitotic activity and especially aiming to identify conditions that suppress cell’s viability as a consequence of premature inactivation of the spindle assembly checkpoint, a conserved signalling pathway monitoring fidelity of mitosis. Finally, we have launched a project to explore the development of resistance to microtubule-drugs, a growing clinical problem in the treatment of cancer. Acquired resistance to mt-drugs has links to malfunction of tubulin and mitotic checkpoint proteins but these mechanisms are poorly understood.

         

Competence

Errors during cell division may result in unequal distribution of DNA between the daughter cells. Gain or loss in the number of chromosomes of the genome is a known cause for miscarriages and birth defects in human, and a hallmark of cancer. We are investigating the spindle assembly checkpoint (also known as the mitotic/kinetochore checkpoint) that monitors interactions between the spindle microtubules and kinetochores, the microtubule binding platforms of chromosomes. If mistakes occur in the microtubule-kinetochore connections, the mitotic checkpoint becomes active and prevents separation of sister chromatids until errors in the chromosome alignment are corrected. Although the main principles of the spindle assembly checkpoint are well documented many molecular details remain to be explored.

One essential element in mitotic signalling is the Chromosome Passenger Complex (CPC) required for ordered progression of mitosis and execution of cytokinesis. We are especially interested of the CPC's catalytic subunit, Aurora B kinase, that promotes bipolar microtubule-chromosome associations and its associate molecule Incenp that stimulates the kinase activity of CPC. The specific question we wish to answer is how members of CPC proteins interact with each other and how they contribute to mitotic checkpoint signalling. The findings are expected to catalyze cancer drug discovery by identification of new possibilities for Aurora B inhibition.

In another set of projects, we are focusing to identification of novel anti-mitotic therapeutics. In particular, we have designed and executed focused HTS to find small compounds, siRNAs and miRNAs that inhibit the function of mitotic checkpoint (override of chemically induced mitotic block) or compounds that are functional analogs of experimental anticancer drug candidates. We have identified several lead compounds, siRNAs and miRNAs that are currently under further investigations using various cell-based and in vitro assays.

Lastly, in a collaborative project with Prof. Olli Kallioniemi we have identified gene copy number and gene expression alterations in parental lung and ovarian cancer cell lines and their microtubule-drug resistant variants. To directly link these genomic findings with a drug efflux pump independent mechanisms of action of microtubule-drug resistance, we are testing if re-expression of the genes lost from the drug-resistant variant cell lines will re-sensitize them to microtubule-drugs, and to silence the same genes alone or in combinations in the parental lines to determine if their lost drives development of microtubule-drug resistance. Other factors that we have recently discovered to affect the sensitivity to microtubule-drugs are specific tubulin isoforms whose loss-of-function leads to abnormal architecture of the mitotic spindle and precocious inactivation of the mitotic checkpoint causing formation of multinucleated progeny cells. We expect to identify novel molecular mechanisms for the microtubule-drug insensitivity. These findings may have diagnostics value in the development of individually optimised therapeutic regimens for cancer patients and for design of new class of microtubule-drugs that selectively target taxane-resistant tumours.


Additional information

Marko Kallio
Principal Scientist, Team Leader
+358 20 722 2810