Donita C. Brady, Ph.D.

faculty photo
Harrison McCrea Dickson, M.D. and Clifford C. Baker, M.D. Presidential Professor
Department: Cancer Biology

Contact information
421 Curie Blvd.
Room 612 BRB II/III
Philadelphia, PA 19104
Office: 215-573-9705
Fax: 215-573-6725
Lab: 215-573-9706
Education:
B.S. (Chemistry)
Radford University, Radford, VA, 2003.
Ph.D. (Pharmacology)
University of North Carolina at Chapel Hill, 2008.
Permanent link
 
> Perelman School of Medicine   > Faculty   > Details

Description of Research Expertise

Research Interests:
The research interests of our laboratory lie at the intersection of cancer biology, signal transduction, and metal homeostasis.

Keywords:
Cancer Biology, Metal Homeostasis, Signal Transduction, Kinases, Small GTPases, Pharmacologic Interventions, Genetically Engineered Mouse Models

Research Details:
The Brady Lab is part of the Department of Cancer Biology, the Abramson Family Cancer Research Institute, and the Abramson Cancer Center 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.

Lab Members:
Graduate Students:
Caroline Davis, B.S.
Tiffany Tsang, B.A.
Postdoctoral Fellows:
Katherine Alwan, Ph.D.
Xingxing Gu, Ph.D.
Research Technician:
Gavin Bond
Administrative Coordinator:
Deb Sneddon
dsneddon@upenn.edu
215-573-2281
Alumni:
Prince Addai
Farrah Alkahleel
Victoria Belka
Jessica Blanchard
Tiyanna Brown
Julianne Davis
Jeffrey Gordon
Danielle Greenberg
Nicole Harrington
Greis Kapexhiu
Yae-Jin Kim
Calvin Nguyen
Jessica Posimo
Gabriel Rodriguez
Jaimarie Sostre Colon
Debbie Spivak
Rotation Projects:
Rotation projects are available in each area of interest in the lab. Please contact Dr. Brady for details.

Selected Publications

Davis, C.I., Gu, X., Kiefer, R. M., Ralle, M., Gade, T.P., & Brady D.C.: Altered copper homeostasis underlies sensitivity of hepatocellular carcinoma to copper chelation. Metallomics 12(12): 1995-008, December 2020.

Blockhuys, S., Brady D.C., & Wittung-Stafshede, P.: Evaluation of copper chaperone ATOX1 as prognostic biomarker in breast cancer. Breast Cancer 27(3): 505-509, May 2020.

Kim, Y.J., Tsang, T., Posimo, J.M, Anderson, G.R., & Brady, D.C.: Inhibition of BCL2 family members increases the efficacy of copper chelation in BRAFV600E-driven melanoma. Cancer Res 80(7): 1387-1400 April 2020.

Tsang, T.*, Posimo, J.M.*, Guidiel, A.A., Cicchini, M., Feldser, D.M., & Brady D.C.: Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma. Nat Cell Biol 22(4): 412-424, April 2020 Notes: (* shared first authorship).

Kim, Y.J., Bond, G.J., Tsang, T., Posimo, J.M, Busino, L., & Brady, D.C.: Copper chaperone ATOX1 is required for MAPK signaling and growth in BRAF mutation-positive melanoma. Metallomics 11(8): 1430-1440 August 2019

Rasool, R.U.*, Natesan, R.*, Deng, Q.*, Aras, S., Lal, P., Effron, S.S., Mitchell-Velasquez, E., Posimo, J.M., Carskadon, S., Baca, S.C., Pomerantz, M.M., Siddiqui, J., Schwartz, L.E., Lee, D.J., Palanisamy, N., Narla, G., Den, R.B., Freedman, M.L., Brady, D.C., & Asangani, I.A.: CDK7 Inhibition Suppresses Castration-Resistant Prostate Cancer through MED1 Inactivation. Cancer Discov 9(11): 1538-1555, November 2019 Notes: (* shared first authorship).

Chung, C.Y.*, Posimo, J.M.*, Lee, S.*, Tsang, T.*, Davis, J.M., Brady, D.C.#, & Chang, C.J.#: Activity-based ratiometric FRET probe reveals oncogene-driven changes in labile copper pools induced by altered glutathione metabolism Proc. Natl. Acad. Sci. U. S. A. 116(37): 18285-18294, September 2019 Notes: (* shared first authorship or # shared corresponding author).

Katona, B.W., Glynn, R.A., Paulosky, K.E., Feng, Z., Davis, C.I., Ma, J., Berry, C.T., Szigety, K.M., Matkar, S., Liu, Y., Wang, H., Wu, Y., He, X., Freedman, B.D., Brady, D.C., & Hua, X: Combined menin and EGFR inhibitors synergize to suppress colorectal cancer via EGFR-independent and calcium-mediated repression of SKP2 transcription. Cancer Res 79(9): 2195-2207 May 2019.

Rivera-Reyes, A., Ye, S., Marino, G., Egolf, S., Ciotti G., Chor S., Liu Y., Posimo, J.M., Park, P.M., Pak, K., Sostre-Colon, J., Tameire, F., Leli, N.M., Koumenis, C., Brady, D.C., Mancuso, A., Weber, K., Gladdy, R., Qi, J., Eisinger-Mathason, T.S.K. : The YAP1-NF-kB axis promotes sarcomagenesis by inactivating circadian clock-mediated unfolded protein responses and autophagy. Cell Death Dis 9(11), October 2018.

Sadeghi R.S., Kulej, K., Kathayat, R.S., Garcia, B.A., Dickinson, B.C., Brady, D.C.#, & Witze, E.S.# : Wnt5a Signaling Induced Phosphorylation Increases Acyl Protein Thioesterase 1 Activity and Promotes Melanoma Metastatic Behavior. Elife April 2018 Notes: (# shared corresponding author).

back to top
Last updated: 05/03/2021
The Trustees of the University of Pennsylvania