Genetic instability is hallmark of many diseases including neuro-developmental disorders and cancer. The origins of genetic instability can be multiple and influence cell and tissue outcome in a cell specific manner. Moreover, underlying vulnerabilities of genetic instability can be translated into what could be interpreted as opposite behaviours such as poor viability or loss of fitness and proliferative advantages, putting in evidence biological paradoxes worth being understood.
We use a diversity of model systems including in vivo animal experimentation such as Drosophila and mouse, mammalian primary tissue culture, human brain organoids and human cell culture combined with state-of-the-art microscopy and quantitative imaged based methodologies to understand causes and consequences of genetic instability. We are particularly motivated to reveal the principles that rule cell proliferation during development and how genetic instability contributes to the onset of disease.
Mitotic spindle morphogenesis and function
The mitotic spindle is multiple component machinery made of microtubules and its associated proteins and motors. The mitotic spindle assembles in a bipolar manner to ensure faithful chromosome segregation during mitosis.
Our work has revealed specific developmental stage factors that contribute to spindle morphogenesis and therefore mitotic fidelity in mammalian neural stem cells. Mutations in genes encoding mitotic spindle components are frequently found in a genetic disorder called primary recessive microcephaly. Using time lapse microscopy combined with micropattern technology and quantitative imaging, we are now investigating which extrinsic biomechanical parameters influence mitotic spindle architecture and in which way these influence chromosome behaviour during mitosis and brain size.
Polyploidy paradox
Polyploidy, the multiple of the entire chromosome set is a strategy used during development to increase metabolic capacity. However, when induced in cells that should not be polyploid, polyploidy leads to genetic instability, which is at the basis of several human tumors.
We want on one hand to understand the mechanisms required to accompany cell growth and ploidy increase during development to decipher scaling up rules. On the other hand we focus on identifying the link between polyploidy and genetic instability. We use microscopy approaches combined with single cell sequencing to identify the extent of genetic instability alterations that follow non-programmed polyploidy. Using genetic screens we have also identified key proteins required to maintain the proliferative capacity of non-programmed polyploid cells. Our projects expose important weaknesses and strengths of the polyploid status.
Centrosome number alterations in cancer
Centrosomes are the major microtubule organizing centers of animal cells. Centrosome number Is tightly regulated during the cell cycle. Using animal models our work and the work of many labs has shown that the presence of more than two centrosomes in a cell, centrosome amplification can induce tumors due to defects in cell division and the consequent generation of aneuploid karyotypes.
Using quantitative cell biology approaches to characterize the centrosome status in human epithelial ovarian cancers we have found several centrosome numerical defects. Combined with RNAseq approaches, single cell genome sequencing and long term imaging approaches, we are now investigating how these defects influence cancer cell behaviour and proliferative capacity.
