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Mutant p53 promotes epithelial-mesenchymal plasticity and enhances metastasis in mammary carcinomas of WAP-T mice

Significance statement

Metastatic processes require tumor cells to assume a state of epithelial-mesenchymal plasticity (EMP), i.e. the ability to switch from an epithelial to a mesenchymal phenotype (epithelial-mesenchymal transition (EMT) and back to an epithelial phenotype by mesenchymal-epithelial transition (MET) (see Figure1). WAP-T mammary carcinomas arising in bi-transgenic WAP-T x WAP-mutp53 mice show strongly enhanced metastasis, resulting from modulation of expression of genes involved in the oncogenic epithelial-mesenchymal transition (EMT) gene network by mutant p53 (mutp53). Despite expression of EMT-inducing genes, bi-transgenic tumors display the same epithelial phenotype as WAP-T tumors arising in mono-transgenic WAP-T mice. In contrast, this EMT gene signature induces a strong mesenchymal phenotype in WAP-T tumor cells ectopically expressing mutant p53 in vitro. However, tumors arising from such cells after orthotopic transplantation assume the same epithelial phenotype as tumors arising in mono- or bi-transgenic WAP-T and WAP-T x WAP-mutp53 mice, respectively. This indicates that mutant p53 mediated expression of an EMT gene signature not automatically leads to EMT, but requires additional factors for inducing a mesenchymal phenotype. Such factors lack in cell culture, but are present in vivo, where EMP is controlled not only tumor cell internal factors, but also by factors of the tumor microenvironment. Our data thus confirm that mutant p53 enhances the metastatic capacity of mouse WAP-T mammary carcinomas by inducing an EMT gene signature that enhances EMP of the tumor cells, i.e. the probability for switching between EMT and MET processes, respectively, as outline in Figure 1.

Figure Legend

This diagram demonstrates the reversible switch of WAP-T tumor cells from an epithelial phenotype, characterized by high expression of Epcam, to a mesenchymal phenotype, characterized by high expression of vimentin by epithelial-mesenchymal transition (EMT) and back by mesenchymal-epithelial transition (MET). This epithelial-mesenchymal plasticity (EMP) is enhanced by mutant p53 (mutp53).

Mutant p53 promotes epithelial-mesenchymal plasticity and enhances metastasis in mammary carcinomas of WAP-T mice

 

 

 

 

 

 

 

 

 

Journal Reference

Lenfert E, Maenz C, Heinlein C, Jannasch K, Schumacher U, Pantel K, Tolstonog GV, Deppert W, Wegwitz F.

Int J Cancer. 2015 Mar 15;136(6):E521-33.

Department for Tumor Biology, University Medical Center Hamburg-Eppendorf (UKE), D-20246, Hamburg, Germany; Department of Tumor Virology, Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, D-20251, Hamburg, Germany.

Abstract

To study the postulated mutant p53 (mutp53) “gain of function” effects in mammary tumor development, progression and metastasis, we crossed SV40 transgenic WAP-T mice with mutant p53 transgenic WAP-mutp53 mice. Compared to tumors in monotransgenic WAP-T mice, tumors in bitransgenic WAP-T x WAP-mutp53 mice showed higher tumor grading, enhanced vascularization, and significantly increased metastasis. Bitransgenic tumors revealed a gene signature associated with the oncogenic epithelial-mesenchymal transition pathway (EMT gene signature). In cultures of WAP-T tumor-derived G-2 cancer cells, which are comprised of subpopulations displaying “mesenchymal” and “epithelial” phenotypes, this EMT gene signature was associated with the “mesenchymal” compartment. Furthermore, ectopic expression of mutp53 in G-2 cells sufficed to induce a strong EMT phenotype. In contrast to these in vitro effects, monotransgenic and bitransgenic tumors were phenotypically similar suggesting that in vivo the tumor cell phenotype might be under control of the tumor microenvironment. In support, orthotopic transplantation of G-2 cells as well as of G-2 cells expressing ectopic mutp53 into syngeneic mice resulted in tumors with a predominantly epithelial phenotype, closely similar to that of endogenous primary tumors. We conclude that induction of an EMT gene signature by mutp53 in bitransgenic tumors primarily promotes tumor cell plasticity, that is, the probability of tumor cells to undergo EMT processes under appropriate stimuli, thereby possibly increasing their potential to disseminate and metastasize.

© 2014 UICC.

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