Harnessing Chemical Interactions to Explore Tumor Cell Biological Responses to Fluctuations in Metal and Micronutrient Availability

NIH Director’s Lecture | Wednesday, February 12, 2025 | 2:00 to 3:00 p.m. ET

Donita C. Brady, Ph.D.

Presidential Associate Professor, Department of Cancer Biology

Department of Cancer Biology Associate Investigator

Perelman School of Medicine University of Pennsylvania

bradyd@pennmedicine.upenn.edu

Website

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.

Summary

The Brady Lab at the University of Pennsylvania focuses on two critical areas of cancer biology: the role of metal signaling and protein function in cancer development and treatment. Their research on metal signaling investigates how dietary metals and their regulation influence cellular processes, metabolic pathways, and stem cell activity, aiming to uncover how disruptions in metal balance may drive cancer. Additionally, the lab explores protein-driven cancer mechanisms using their innovative PEAR platform, which tracks protein function to reveal treatment responses and identify drug targets beyond genetic mutations. This work aims to advance precision oncology and improve therapeutic strategies for cancer patients.

Learning Objectives: 

1. Understand the Role of Metal Signaling in Cancer Biology: Learners will explore how dietary metals and their regulation impact cellular processes, metabolic pathways, and stem cell activity, as well as how disruptions in metal balance contribute to cancer development.
2. Analyze Protein-Driven Cancer Mechanisms and Precision Oncology Approaches: Learners will examine how the PEAR platform identifies protein function changes in cancer cells, reveals new drug targets, and enhances therapeutic strategies beyond genetic analysis.

https://videocast.nih.gov/watch=55019