Ongoing gain or losses of chromosomal material is a common characteristic of cancers. This chromosomal instability (CIN) is not tolerated by normal cells, but for cancer cells it provides a significant increase in the mutation rate with each cell division, leading to the rapid evolution of adaptive, highly aberrant clones that are typically hard to treat. We have been screening for vulnerabilities in cells with chromosomal instability, and have identified several signalling pathways that affect cell metabolism.
We have published work showing that genomic disruption affects glycolysis and mitochondrial output. We identified that PAS kinase can be depleted to prevent the growth of CIN cells without affecting normally dividing cells. More recently our attention has shifted to pursuing how cells can tell that they are aneuploid, once chromosomal instability has set in. This doubtless includes global, non-specific effects such as altered stoichiometry of protein complexes and elevated rates of protein misfolding, but we have evidence to suggest that metabolic mechanisms contribute.
We will present data on the metabolic vulnerabilities that we have identified in cells with induced CIN, as well as models for how Parylation, the sex determination machinery and one-carbon metabolism play a role.