Exploiting a novel link between metabolism and acetylation to predict and to treat metastasis formation

Metastasis formation is the leading cause of death in breast cancer
patients with nearly 30% of patients developing metastases.
Unfortunately, we currently cannot predict which patient will develop
metastases due to our limited understanding of how cancer cells gain
metastatic capacity. This greatly reduces the application of
personalized follow up screening and preventative measures. We
have discovered that increased concentrations of the metabolite
acetyl-CoA and consequently histone acetylation greatly potentiates
the ability of breast cancer cells to metastasize. Thus, we
hypothesize that elevated acetyl-CoA and histone acetylation in
primary cancers predict metastasis risk and can be targeted for
therapy once metastases arise. Thus, we will define 1) To which
extent acetyl-CoA and histone acetylation are predictive of
metastasis formation, 2) How histone acetylation drives metastatic
capacity and 3) Which organ-specific metabolic factors sustain
acetyl-CoA-mediated histone acetylation. To address these
questions, we will exploit ChIP-, ATAC-, and RNA-sequencing,
spatial/bulk metabolomics, multiplex IHC and pharmacologic
interventions in breast cancer cell lines, mouse models and human
breast cancer samples. In conclusion, we will deliver a mechanistic
understanding of how breast cancer cells gain metastatic capacity.
We expect that this project will contribute in the long-term to an
improved prediction of metastasis risk and to therapeutic strategies
against metastases