Mutant p53 regulates cancer cell invasion in complex three-dimensional environments through mevalonate pathway–dependent Rho/ROCK signaling
Abstract
Certain TP53 mutations can confer neomorphic gain of function (GOF) activities to the p53 protein that affect cancer progression. Yet the concept of mutant p53 GOF has been challenged. Here, using various strategies to alter the status of mutant versions of p53 in different cell lines, we demonstrate that mutant p53 stimulates cancer cell invasion in three-dimensional environments. Mechanistically, mutant p53 enhances RhoA/ROCK-dependent cell contractility and cell-mediated extracellular matrix (ECM) reorganization via increasing mevalonate pathway–dependent RhoA localization to the membrane. In line with this, RhoA-dependent proinvasive activity is also mediated by IDI-1, a mevalonate pathway product. Further, the invasion-enhancing effect of mutant p53 is dictated by the biomechanical properties of the surrounding ECM, thereby adding a cell-independent layer of regulation to mutant p53 GOF activity that is mediated by dynamic reciprocal cell–ECM interactions. Together our findings link mutant p53 metabolic GOF activity with a context-dependent invasive cellular phenotype.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (13)
Asja Guzman
Department of Biological Sciences, Columbia University
Tatsuya Kawase
Astellas Pharma Inc.
Alexander J. Devanny
Department of Chemistry, Columbia University
Gizem Efe
Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center
Raúl Navaridas
Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center
Karen Yu
Department of Physics, Columbia University
Kausik Regunath
Department of Biological Sciences, Columbia University
Iris G. Mercer
Department of Chemistry, Columbia University
Rachel C. Avard
Department of Chemistry, Columbia University
Rafaela Muniz de Queiroz
Department of Biological Sciences, Columbia University
Anil K. Rustgi
Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center
Laura J. Kaufman
Department of Chemistry
Carol Prives
Department of Biological Sciences, Columbia University