Defining the roles of mutant p53 and Mdm2 in metastasis

PROJECT SUMMARY Tumor cell invasion and metastasis are ultimately critical determinants of cancer related mortality. Innovative approaches are required to leverage biologically based mechanistic insights into the potential for new translational biomarkers, prognostic stratification and therapeutics. Certainly, mutations in the tumor suppressor TP53 are important in tumor initiation, microenvironmental landscaping and metastasis. Less is known about the mechanisms of different TP53 mutations in fostering metastatic colonization and outgrowth. MDM2 is important in the regulation of wild-type p53, but its role, along with its heterodimer MDMX, in the context of mutant p53 or p53 null backgrounds, requires elucidation in metastasis biology. The overarching goal of this Project is to elucidate the differential contributions of specific missense p53 contact and conformational mutations and MDM2/X functions, independently or in concert, in tumor invasion and metastasis. We hypothesize that different p53 mutations and MDM2/X will differentially contribute to metastatic abilities of tumor cells. This hypothesis will be addressed by the following interrelated Specific Aims through the deep and already existing interactions, and collaborations between the Prives and Rustgi labs at Columbia University, using complementary in vitro and in vivo model systems: AIM 1. To elucidate the cell autonomous mechanisms mediated by specific missense TP53 mutations that contribute to tumor cell invasion and metastasis; AIM 2: To determine the effects of the extracellular matrix upon tumor cells with different missense TP53 mutations upon invasion, as a prelude to metastasis; and AIM 3: To determine the p53- independent roles of MDM2/X in tumor metastasis. Our project has specific interactions with Projects 1, 2 and 4 through sharing of conceptual frameworks, reagents, model systems and technical expertise, which promote synergy. We will utilize the Cores that will accelerate our progress in achieving our vision.