MDA S13.8116B (Unit 1010)
The University of Texas MD Anderson Cancer Center
Department of Genetics
Cancer cells evolve sequentially through the stepwise acquisition of detrimental mutations that collectively wreak havoc on cellular homeostasis. How do these deranged cells minimize the cost of mutation and tap into the reservoir of acquired mutations to form tumors, metastasize and resist therapies? We focus on a sentinel of protein homeostasis, the molecular chaperone HSP90, and how it links genes and environment to shape the course of cancer evolution.
We are seeking strong candidates for two high-impact cross-disciplinary PhD projects.
Project 1. Functional Genomics
This project investigates the genetic architecture of HSP90-dependent traits and how they evolve within tumors. We demonstrated that HSP90 acts as a protein folding “buffer” in human cells that mitigates the deleterious effects of mutations. Proteins with HSP90-buffered mutations retain normal function at basal conditions, but lose activity when the HSP90 function is reduced. A paradigmatic example of HSP90-buffering we identified involved a case of identical twins with Fanconi Anemia, which is a severe cancer predisposition and premature aging syndrome (Karras et al., Cell 2017). The candidate will use our established system to study how HSP90 influences the sensitivity of cancer cells to chemotherapy, employing functional genomics, high-throughput biochemistry and quantitative genetics in budding yeast, CRISPR-engineered cancer cell lines and mice. Understanding the evolving architecture of HSP90-dependent traits will help develop strategies to target HSP90 to slow tumor evolution.
Project 2. Chemical Systems Biology
This project explores the molecular underpinnings of HSP90’s unusual environmental sensitivity. Seemingly benign stressors, such as fever, uncover HSP90-buffered mutations thereby inducing mutant-specific phenotypes (Karras et al., Cell 2017). We performed chemical screens and identified diverse chemicals that modulate HSP90 activity, among which FDA approved drugs and food products. The candidate will characterize the mechanism of action of hits from our screens by employing a multi-omics approach integrating chemical biology and cutting-edge proteomics, along side established chemical genetics screening platforms in engineered yeast and human patient cells (Karras & Jentsch, Cell 2010; Karras et al., Cell 2017). Tapping into the wealth of results available to our laboratory, the student will elucidate the mechanisms that link HSP90 function to the environment and will develop new tools to harness the HSP90 machinery for precision medicine.
Education & Training
Ph.D., Ludwig Maximilian University of Munich, 2010
Protein Homeostasis and Cancer Evolution