Mutant p53 regulates cancer cell invasion in complex three-dimensional environments through mevalonate pathway-dependent Rho/ROCK signaling
成果类型：
Article
署名作者：
Guzman, Asja; Kawase, Tatsuya; Devanny, Alexander J.; Efe, Gizem; Navaridas, Raul; Yu, Karen; Regunath, Kausik; Mercer, Iris G.; Avard, Rachel C.; de Queiroz, Rafaela Muniz; Rustgi, Anil K.; Kaufman, Laura J.; Prives, Carol
署名单位：
Columbia University; Astellas Pharmaceuticals; Columbia University; Columbia University; Cornell University; Weill Cornell Medicine; NewYork-Presbyterian Hospital; Columbia University
刊物名称：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN/ISSBN：
0027-8424; 1091-6490
DOI：
10.1073/pnas.2424904122
发表日期：
2025-10-28
页码：
E2424904122
关键词：
mutant p53
invasion
Rho/ROCK signaling
mevalonate pathway
IDI-1
DRIVES INVASION
small-molecule
RHOA ACTIVITY
up-regulation
mouse models
OF-FUNCTION
gain
migration
metastasis
collagen
摘要：
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.
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