EMT Inducers Catalyze Malignant Transformation of Mammary Epithelial Cells and Drive Tumorigenesis towards Claudin-Low Tumors in Transgenic Mice

Abstract

The epithelial-mesenchymal transition (EMT) is an embryonic transdifferentiation process consisting of conversion of polarized epithelial cells to motile mesenchymal ones. EMT–inducing transcription factors are aberrantly expressed in multiple tumor types and are known to favor the metastatic dissemination process. Supporting oncogenic activity within primary lesions, the TWIST and ZEB proteins can prevent cells from undergoing oncogene-induced senescence and apoptosis by abolishing both p53- and RB-dependent pathways. Here we show that they also downregulate PP2A phosphatase activity and efficiently cooperate with an oncogenic version of H-RAS in malignant transformation of human mammary epithelial cells. Thus, by down-regulating crucial tumor suppressor functions, EMT inducers make cells particularly prone to malignant conversion. Importantly, by analyzing transformed cells generated in vitro and by characterizing novel transgenic mouse models, we further demonstrate that cooperation between an EMT inducer and an active form of RAS is sufficient to trigger transformation of mammary epithelial cells into malignant cells exhibiting all the characteristic features of claudin-low tumors, including low expression of tight and adherens junction genes, EMT traits, and stem cell–like characteristics. Claudin-low tumors are believed to be the most primitive breast malignancies, having arisen through transformation of an early epithelial precursor with inherent stemness properties and metaplastic features. Challenging this prevailing view, we propose that these aggressive tumors arise from cells committed to luminal differentiation, through a process driven by EMT inducers and combining malignant transformation and transdifferentiation.

Epithelial–mesenchymal plasticity in carcinoma metastasis

“…Twist1 was also shown to override oncogene-induced senescence and apoptosis by binding to p53 and promoting its degradation (Valsesia-Wittmann et al 2004;Ansieau et al 2008;Lee and Bar-Sagi 2010;Piccinin et al 2012). By inhibiting p53, Twist1 was able to cooperate with oncogenes such as Her2 and H-ras to promote malignant transformation (Valsesia-Wittmann et al 2004;Ansieau et al 2008;Morel et al 2012;Piccinin et al 2012), suggesting a potential role of EMT genes in tumor initiation.…”

Reprogramming during epithelial to mesenchymal transition under the control of TGFβ

“…Interestingly, EMT-TFs like Twist1 and ZEB1/2 interfere with key pathways regulating cell survival, such as the p53, pRb and PP2A phosphatase, resulting in the development of breast cancers that have characteristic enrichment in stem-like features. 139 Resistance to cell death is indeed an important feature not only during the process of EMT, but also for the generation of CSCs. 140 Based on a variety of findings, it could be argued that EMT and changes in differentiation induce stem like properties in cancer cells, as opposed to the hypothesis of CSCs being derived from malignant transformation of stem-like progenitor cell types in the mammary gland.…”

Plasticité des cellules cancéreuses et dissémination métastatique

“…Ces structures spécialisées des cellules invasives, sont des régions de réorganisation du cytosquelette d'actine dans lesquelles se concentre une MMP (la MT1-MMP [membrane-type matrix metalloproteinase 1] ou MMP14) essentielle à l'invasion et à la dégradation de la matrice [13]. De façon importante, l'expression des FT-TEM procure aux cellules tumorales une capacité de survie accrue, en particulier en inhibant les voies onco-suppressives dépendantes de p53 et de Rb (retinoblastoma protein) [5,14,15,41] (➜). Cette propriété favorise le développement de la tumeur primaire, et protège les cellules tumorales en cours d'invasion et de dissémination contre les stress associés aux processus d'anoïkie (mort cellulaire consécutive à la perte de contacts cellules-cellules et au détachement de la matrice extracellulaire sous-jacente), d'invasion et de dissémination.…”

“…La TEM est nécessaire à plusieurs étapes critiques de la morphogenèse aboutissant à la construction du plan de l'embryon et au développement des organes. Ce processus est contrôlé par des signaux du microenvironnement et orchestré par un réseau de facteurs de transcription (FT-TEM), dont les mieux caractérisés appartiennent aux familles SNAIL, ZEB et TWIST [5,6]. Il consiste en une reprogrammation importante de l'épigénome, impliquant notamment des changements dans la méthylation de l'ADN, des modifications post-traductionnelles des histones, des changements d'expression à l'origine de micrométastases et seulement 1 % de ces micromé-tastases progresse jusqu'à un stade macroscopique [4].…”