Cancer cells display remarkable plasticity allowing them to adapt to ever changing environments. A key feature of this plasticity is their ability to rewire core metabolic networks to provide a steady source of energy and building blocks needed for rapid growth. This demand for energy produces byproducts including reactive oxygen species (ROS) that alter the function of proteins, DNA and lipids, and if left unchecked, results in oxidative stress and impairs cancer cell viability. We now appreciate that ROS and other reactive metabolites are not just static entities within a cell, but represent dynamic signaling molecules that alter cellular and organismal physiology. Despite decades of research, we know surprisingly little about about ROS sensing and signaling and how this class of molecules regulates protein function within the cell. Our long term goals are to understand how cells respond to altered metabolic states and to pharmacologically modulate these pathways in diseases where they are deregulated.
Redox control pathways
The NRF2/KEAP1 pathway functions as the master regulator of the cellular anti-oxidant response and is deregulated in a large number of cancers. Our studies focus on understanding how deregulation of this pathway promotes the proliferation of non small cell lung cancers where this pathway is commonly mutated. Towards this end, we have identified that NRF2 can regulate protein function independently of its control of protein expression. Research in our lab aims to identify how this NRF2-mediated redox regulation alters cellular function as well as the identification of new regulators of this pathway using proteomic and genomic methodologies.
A second area of research in our lab is identifying new ROS sensors. ROS production occurs in multiple organelles including the mitochondria, ER, nucleus and lysosome. How these organelles sense changes in ROS levels and maintain ROS homeostasis is poorly understood. To address these questions we employ chemical proteomic platforms (isoTOP-ABPP) that allow us to identify global changes in cysteine reactivity upon changes in organelle ROS. In a complementary series of study we are developing an innovative suite of metabolic tools that will allow us to identify the reactive metabolites that post-translationally modify proteins. These studies are already illuminating how core metabolic pathways exert control over the function of proteins and pathways not generally connected to metabolism.
Druggable co-dependencies in cancer
While major drivers of oncogenic proliferation have been identified, modulators of these core pathways which are required for cancer proliferation are still being discovered. Our research seeks to identify these 'co-dependecies' and small molecule inhibitors that can regulate their function. Unhindered by the conventional notions of what proteins are considered druggable we employ Protein Druggability Mapping (PDM), a chemical proteomic platform that allows us to identify these co-dependencies and corresponding inhibitors for them. One particular focus for our group is transcription factor (TF) signaling pathways that respond to altered metabolic states. These pathways represent a diverse class of proteins that underlie basic physiological process and are often hijacked by multiple cancers, becoming indispensable for their proliferation. In contrast to their kinase counterparts, most TF pathways are difficult to pharmacologically modulate, representing not only a dearth in potential therapeutic options but also an incomplete understanding of their biological functions and regulation of metabolic and stress pathways. Using PDM we have identified multiple druggable proteins within TF pathways regulating stress and metabolic networks upregulated in cancer. Current studies are centered on elucidating their functions and developing potent inhibitors for these transcriptional and metabolic targets.
We address how cells respond to different metabolic states using next-generation molecular and chemical proteomic platforms. Chemical proteomics (isoTOP-ABPP platform) marries chemical probes that specifically react with protein residues (i.e. cysteine/lysine) with a proteomic output, providing a rapid global view of changes in protein activity, redox state and drubbabilty at residue-level resolution. By combining these technologies with cutting-edge cell and molecular approaches (i.e. CRISPR-screens and organelle-IPs), we have an unparalleled ability to mechanistically dissect how cells respond and adapt to metabolic stress.