Abstract SY32-02: Modulation of wild-type p53 activity in cancer cells and in the tumor microenvironment
Authors: Oren Moshe , Arandkar Sharathchandra , Benor Gal , Furth Noa , Aylon Yael , Domany Eytan 
Published: August 2019

While the TP53 gene is mutated in about half of all human cancer cases, it remains wild type (wt) in the other half, suggesting that its tumor suppressor activities are either abrogated or circumvented in the latter cases. Moreover, while early evidence indicates that p53 can also exert non-cell-autonomous tumor suppressive activities in the tumor stroma, p53 typically remains wt in stromal cells. These observations raise the question of what exactly happens to p53 in tumors where the TP53 gene is not mutated. The two main alternative scenarios that come to mind are: 1. The protein is retained in functional state, but is unable to exert measurable biological effects in particular contexts or particular cell types; 2. The protein loses its functionality, either because it is not expressed at all (e.g. the gene is silenced or the protein is degraded), or because it is subjected to inhibitory molecular processes (e.g. protein-protein interactions or post-translational modifications) that deprive it of its functionality. In both scenarios, further depletion of the endogenous wtp53 is not expected to have significant biological consequences. Recent work from our lab has provided support for a third scenario, wherein the p53 protein is wt by sequence, but nevertheless acquires properties that are usually ascribed to cancer-associated mutant p53 isoforms, namely oncogenic gain-of-function properties. This has been demonstrated in human mammary epithelial cells in which key components of the Hippo tumor suppressor pathway have been silenced, as well as in cancer-associated fibroblasts. In both situations, depletion of the endogenous wtp53 protein leads to attenuation of features associated with cancer aggressiveness, such as cancer cell migration and invasion, implying that the wtp53 of those cells actually contributes to a more aggressive cancer phenotype. We thus proposed that such “oncogenic rewiring” converts wtp53 from tumor suppressor to cancer promoter. In an attempt to evaluate whether rewiring of wtp53 can be observed in actual human tumors, we interrogated gene expression profiles and pathway deregulation patterns in the METABRIC breast cancer dataset as a function of TP53 mutation status (subsequently validated also on the TCGA dataset). As expected, a gene expression signature that distinguishes between tumors that carry TP53 mutations and those that retain wt TP53 could be defined and validated. Interestingly, a small subset of wt TP53 tumors nevertheless displayed gene expression and pathway deregulation patterns that were markedly similar to those observed in TP53-mutated tumors, and distinct from the patterns that are characteristic of the bulk of wt TP53 breast tumors. Conceivably, this subset of tumors may represent situations where the p53 protein is not expressed or is rapidly eliminated. However, at least in several of those cases, p53 expression was observable by immunohistochemistry, suggesting that the wtp53 protein is rewired rather than absent. Analysis of the transcriptional profile of this “pseudomutant” subset of wt TP53 tumors identified a subset of pathways that are preferentially deregulated in those tumors as compared to the other wtp53 tumors and the TP53-mutated tumors, raising the possibility that their deregulation may play a role in the rewiring of wt p53 into a “pseudomutant” state. Initial experiments aimed to address this possibility in human breast cancer cells will be presented.

Citation Format: Moshe Oren, Sharathchandra Arandkar, Gal Benor, Noa Furth, Yael Aylon, Eytan Domany. Modulation of wild-type p53 activity in cancer cells and in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY32-02.