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FRIMEDBIO-Fri med.,helse,biol

Ruptured nuclear envelopes in cancer

Alternative title: Skadede kjernemebraner i kreftutvikling

Awarded: NOK 8.0 mill.

The chromosomes in our cells are enclosed within the cell nucleus. A membrane called nuclear envelope surrounds the nucleus and, like a shield, it protects chromosomes from damage and mutations. Cancer cells are characterized by damaged chromosomes. These can often end up outside the nucleus to form aberrant structures called micronuclei and DNA bridges. Similarly to the cell nucleus, micronuclei and DNA bridges are also enveloped by their own membrane. However, recent groundbreaking research has shown that the chromosomes contained in micronuclei and DNA bridges often fragment into many small pieces, causing a dramatic increase of mutations and accelerating disease progression. Why and how chromosome damage escalates so dramatically in micronuclei and DNA bridges is still unclear. In this project, we will determine if the membranes that enclose micronuclei and DNA bridges do not provide the same protection as the membrane surrounding the cell nucleus. We will do this by analyzing what happens to these membranes when they form and when they are damaged. Our aim is to provide a detailed explanation of these mechanisms. This new knowledge can potentially set the grounds for the development of new cancer treatments.

DNA bridges and micronuclei are aberrant cellular structures that stem from uncontrolled cell division, high degree of DNA damage, and chemotoxic treatments. Major breakthroughs have identified them as a source of immune and inflammatory responses in the tumor microenvironment as well as catastrophic chromosomal rearrangements, highlighting an unprecedented role in cancer evolution, metastasis, and response to therapy. Compared to primary nuclei, nuclear envelope integrity at these structures seems defective. Based on our recent work (Vietri et al., Nature 2015; Vietri et al., Nature Cell Biology 2020) and new preliminary observations, we propose to characterize the dynamics and physical properties of the nuclear envelope at chromosome bridges and micronuclei and investigate their contribution to the fate of cancer cells. In this project, we will use cutting-edge laboratory techniques, such as advanced light microscopy, Correlative Light Electron Tomography, Immuno- Electron Tomography, Optogenetics, Mechanobiology devices, in-situ detection of double-strand DNA breaks, and Look-sequencing.

Funding scheme:

FRIMEDBIO-Fri med.,helse,biol