Research Abstract
Transition metals are essential for life. Dysregulation of metal homeostasis contributes to numerous disease states including cancer, neurodegeneration, and various metabolic and rare genetic disorders. Thus, there exists a very high level of interest in understanding the versatile roles of metals in biological processes and in the manifestation and progression of disease. In recent years, the use of genomic and phenotypic screening tools was used to complement the biochemical study of metal biology. These studies, including my own, have challenged the traditional view that metals are solely enzyme co-factors but instead have revealed that transition metals, such as copper, act as dynamic allosteric regulators of cell signaling, growth and cell death. These efforts are leading to a new conceptual framework termed ‘metalloplasia’, that is defined as regulated metal-dependent cell fitness.
The current ongoing projects in the Tsvetkov lab are focused on: (1) Expanding our mechanistic understanding of the recently described, new form of regulated cell-death induced by copper, we termed ‘cuproptosis’ (Tsvetkov et al., Science 2022). (2) Exploring the benefits of copper ionophores as potential anti-cancer therapeutic using both cell-culture, mouse model and human patient sample models. (3) Developing new experimental paradigms aimed at revealing new mechanisms that are regulated by environmental metabolite/nutrient/metal availability and promote cancer cell survival and adaptation to stress (drug-resistance) using both high-throughput chemical and genomic approaches (CRISPR based KO and ORF and small molecule screening libraries) and thorough biochemistry.