Welcome to the Brady Lab
The Brady Lab is part of the Department of Cancer Biology and the Abramson Family Cancer Research Institute in the Perelman School of Medicine at the University of Pennsylvania. Our research program at Penn is founded in a new paradigm in nutrient sensing and protein regulation, termed metalloallostery, where redox-active metals control kinase activity, and is advancing our knowledge in basic science and disease-focused areas. Our focus lies at the intersection of kinase signaling and copper (Cu) homeostasis with the goal of defining the mechanistic features of Cu-dependent kinases to target them in cancer via drug repurposing or development. Kinases directly respond to and, in some cases, sense inputs, like growth factors, nutrients, and metabolites, to relay information to drive complex cellular processes. Aberrant kinase activation disrupts the balance between cell growth and cell death and in turn, can drive cancer initiation and progression. While kinase inhibitors dramatically changed the landscape of cancer treatment, emergence of resistance limits clinical durability. Our discovery that the transition metal Cu, which is acquired as a dietary nutrient and essential for life, activates the canonical MAPK pathway at the level of the MEK1/2 kinases established an evolutionarily conserved, critical mechanistic function for Cu as an intracellular mediator of signaling (Turski & Brady et al. Mol Cell Biol 2012). The direct interaction between Cu and MEK1/2 is the first example of Cu enhancing mammalian kinase activity and exposed a mechanistically distinct vulnerability that can be exploited therapeutically in cancers with aberrant MAPK signaling (Brady et al. Nature 2014). The emergence of this new clinically relevant signaling paradigm highlights the need to understand how redox-active metals interact with signaling pathways and underlines the promise of discovering new modes of kinase regulation as orthogonal therapeutic vulnerabilities.
Brady Lab BMB Ph.D. candidate Caroline Davis and postdoctoral fellow Xingxing Gu collaborated with members of the Gade Lab at University of Pennsylvania and Martina Ralle at Oregon Health & Sciences University to discover altered Cu transporter expression in HCC that elucidated a unique Cu-dependent vulnerability within glycolytic metabolism necessary for tumorigenesis. These findings In Press at Metallomics uncover a clinically tractable alternative treatment to combat HCC by repurposing Cu chelators. Congratulations team!
Congratulations to new Brady Lab postdoctoral fellow Katherine Alwan on completing her PhD in Biochemistry and Molecular Biology from the Blackburn Lab at Oregon Health & Sciences University. Welcome to the Brady Lab!
Congratulations to Brady Lab postdoctoral fellow Yae-Jin Kim on her new job at University of Pittsburgh! Best of luck Yae-Jin!
Brady Lab postdoctoral fellows and Jessica Posimo and CAMB CB Ph.D. candidate Tiffany Tsang worked together to employ high-throughput small molecule screens to unveil a novel collateral drug sensitivity in BRAF-mutant melanoma elicited in combination with Cu chelators in press at Cancer Research. Congratulations team!
Brady Lab CAMB CB Ph.D. candidate Tiffany Tsang and postdoctoral fellow Jessica Posimo worked collaborated with members of the Feldser Lab at University of Pennsylvania to discover that Cu binds to and is required for ULK1/2 activity and, as a consequence, is a critical input for ULK1/2-dependent autophagy. Dual targeting of MAPK signaling and ULK1/2-driven autophagy by limiting Cu availability, and therefore kinase Cu binding decreased oncogenic KRAS-driven tumor growth and survival in press at Nature Cell Biology. Congratulations team!
Department of Cancer Biology Events
Brady Recipient of Penn Medicine Award of Excellence Michael S. Brown New Investigator Research Award
October 27, 2020
Tsang Named 2020 Blavatnik Family Fellow in Biomedical Research
July 1, 2020