Lectures and seminars CCK lecture: Uncovering and rationalizing cancer mutations through protein dynamics simulations

Laura Orellana, PhD, is an Assistant Professor & Group Leader at Dept Oncology/Pathology with her lab at Biomedicum. She heads the Protein Dynamics and Mutation Lab. She is a Cancerfonden Junior Investigator & Vetenskapsrådet Fellow

Research Interests:             

The research of the Orellana group aims to understand protein function and disease mechanisms through conformational dynamics and evolution.

How can a single mutation disrupt protein function and propagate throughout scales, from cells to tissues and the whole organism causing diseases like cancer? How can the change of just a few atoms in an oncogene trigger the formation of a tumor? How is the sequence of a protein related to its shape and function? 

We aim to answer these fundamental questions by exploring the molecular basis of mendelian diseases and cancer at the deepest level, in terms of protein structures and their motions at the atomic scale. 

To reveal the key dynamic information contained in cancer mutation patterns, we develop simulation methods (Front.Mol.Biosciences, 2019; Nat.Comms, 2016) and servers (Bioinformatics, 2019) and integrate them with structural determination techniques (SAXS, cryoEM), in vitro and in vivo experiments. Using this interdisciplinary approach, we discovered that EGFR mutations in brain tumors converge to acquire a similar conformation, which is antagonistic from mutations in lung cancer and respond to different drugs. Our mechanistic insights set a rational basis for synergistic drug combinations that trap this glioblastoma-specific EGFR conformation, triggering tumor regression in animal tumor models (PNAS, 2019; Cancer Cell, 2018). 

Our goal is to go beyond conventional oncogenes like EGFR and perform a complete conformational profiling of tumors, which will be essential to identify, group and rationally target evolutionarily selected mutations with conformation-specific drugs. 

On a broader view, we believe that understanding biomolecular dynamics, protein-protein interactions and folding, and their perturbations in human diseases is essential to connect the structural scale with higher-level observations in molecular biology and medicine and push the boundaries of biophysical research and our understanding of life mechanisms (Nat.Comms., 2021; EMBO Journal; Nature, 2020;  Cancer Cell, 2019)