Defining novel lung cancer drivers through metabolic profiling of the aging metastatic niche

The goal of this project is to define how age-related changes and tumor metabolic changes support the metastatic dissemination of tumor cells.

Importantly, the risk of developing a metastatic disease is two-fold higher in cancer patients above 60-years old compared to younger patients. Efforts to identify metastasis driver mutations have been largely unsuccessful.

Instead, many studies show that cancer cells metastasize by adapting to oxidative stress or by rewiring metabolic pathways. Other reversible mechanisms are likely involved, but remain undefined.

The extent to which age and oxidative stress affect the cross-talk between cancer cells and the metastatic niche is also unknown. Thus, much more work is needed to understand how these factors fluence cancer cells during metastasis.

First, we will perform a CRISPR/Cas9 metabolic screen to identify vulnerabilities in cells that express high levels of the metastatic factor BACH1. We will determine whether lactylation, a metabolic epigenetic mark, is involved in metastasis.

We will also dissect how antioxidants and age influence the metastatic niche, ie, the micro-environment that supports growth of metastatic cells in a secondary organ, using a newly-developed fluorescent labeling system, and single-cell analyses. These studies should markedly increase our knowledge on how cells overcome stress barriers faced during metastasis.

The ultimate goal is to identify new mechanisms that can be targeted for therapeutic purposes.