In vivo CRISPR screen to identify epigenetic regulators of organ-specific breast cancer metastasis
Distant metastases are the leading cause of breast cancer deaths. Yet, our understanding of how breast cancer cells gain metastatic capacity is sparse. Consequently, we only have a limited ability to predict and prevent metastasis formation. Strikingly, I have discovered that increased histone acetylation – an epigenetic reprogramming known to activate gene expression – greatly potentiates the in vivo ability of breast cancer cells to metastasize. I hypothesize that the drivers of histone acetylation modifications have an essential role for cancer cells to colonize the metastatic niche. Consequently, I expect that disruption of the expression of these epigenetic drivers will reveal novel epigenetic dependencies and potential drug targets for metastasis formation. In this project, I will perform a CRISPR/Cas9 loss-of-function screen to knockout epigenetic enzymes in breast cancer mouse models under different metabolic backgrounds. I will sequence metastases from different organs (lung, liver, bone and brain) to determine which gene knockouts are underrepresented and thus which epigenetic regulators are essential for each metastatic site. I will determine the impact of high-fat diet and alcohol consumption on these epigenetic dependencies. I expect to generate strong preliminary data to establish functional and mechanistic studies of important epigenetic drives of organ-specific breast cancer metastases.