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Despite many attempts to replicate these results, the authors have been unable to confirm the original data showing that IL-17 alone or in combination with B cell-activating factor controls the survival of human B cells (Fig. 1a,b).

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Background: Embryonic transcription factors inducers of Epithelial to Mesenchymal Transition (EMT-TFs) are frequently reactivated during tumorigenesis. In addition to promoting metastasis in carcinoma, they favor neoplastic transformation of epithelial cells by enabling escape from oncogene-induced senescence and apoptosis and providing cells with stem-like properties. We recently unveiled different regulation and function of EMT-TFs in melanoma, a highly metastatic neural crest-derived cancer. We observed a switch in expression from SNAIL2 and ZEB2, which are expressed in melanocytes and behave as oncosuppressive proteins to TWIST1 and ZEB1, which are aberrantly reactivated in melanoma and cooperate with BRAFV600E oncogene to induce neoplastic transformation of melanocytes. This switch in EMT-TF expression represents a novel independent factor of poor prognosis in patients with malignant melanoma (Caramel et al, Cancer Cell, 2013). We further investigated the oncogenic properties of TWIST1 and ZEB1 in melanoma development and analyzed the crosstalk with the master regulator of melanoma phenotypic plasticity, the microphthalmia-associated transcription factor MITF. Methods: We first analysed the expression of MITF and TWIST1/ZEB1 in melanoma cell lines and human melanoma specimens by immunohistochemistry. We then studied the role of TWIST1 in melanoma progression in vivo by crossing conditional Twist1 transgenic mice with BRAFV600E/TyrCreERT2 mice. Results: Our data suggest that EMT-TFs control melanoma cell plasticity by modulating MITF level and the associated pathways. High MITF levels maintain the differentiated status of melanocytes, while reduction of MITF expression results in the transition to proliferative and invasive/stem states. TWIST1 and ZEB1 cooperate with BRAF in downregulating MITF concomitantly with the induction of invasion-associated gene signatures. A correlation of MITF expression with TWIST1 and ZEB1 is observed in human melanoma specimens at the intratumoral level. Moreover, while Twist1 enables BRAFV600E-induced senescence escape in primary mouse melanocytes, monitoring of the development of nevi and melanomas in the BRAFV600E mouse model showed more aggressive features in BRAFV600E/Twist1 mice compared to BRAFV600E control mice. Conclusion: Collectively, these data highlight crucial roles for TWIST1 and ZEB1 in promoting cell dedifferentiation and plasticity of non-epithelial cells. By regulating MITF-dependent phenotype switching they contribute to malignant progression of melanoma. Therefore, targeting the EMT-TF network represents an attractive strategy for metastatic melanomas that invariably develop resistance to BRAFV600 targeted therapy. Citation Format: Julie Caramel, Geoffrey Richard, Michelle Houang, Arnaud de la Fouchardiere, Lionel Larue, Richard Marais, Stephane Dalle, Eugene Tulchinsky, Stephane Ansieau, Alain Puisieux. Cell plasticity mediated by EMT-inducing transcription factors contributes to melanoma development. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1144. doi:10.1158/1538-7445.AM2014-1144

The malignant transformation of human epithelial cells is generally described as a multistep process resulting from the accumulation of five to seven rate-limiting changes. Here, we challenge this dogma and demonstrate that this number is radically reduced when cells undergo an epithelial-mesenchymal transition (EMT). EMT is an embryonic transdifferentiation process that consists of the conversion of polarized epithelial cells into motile mesenchymal ones. EMT-inducing transcription factors, including Twist and Zeb proteins, are aberrantly expressed in multiple tumor types and are known to favor the metastatic dissemination process. We demonstrate that, beyond their prometastatic potential, EMT inducers also act as potent drivers of tumorigenesis. We indeed show that the Twist1 EMT-inducing transcription factor promotes breast and skin cancer development in vivo in cooperation with the K-RasG12D oncoprotein. Importantly, in the model of breast tumorigenesis, transgene expression in differentiated mammary epithelial cells leads to the development of undifferentiated tumors exhibiting all the characteristic features of the claudin-low subtype. These observations challenge the concept that this tumor subtype specifically arises from transformation of an early epithelial precursor with inherent stemness properties and metaplastic features. Consistently, oncogenic cooperation assays performed in human mammary epithelial cells with Twist or Zeb EMT-inducers in combination with H-RasG12V generate transformed cell lines displaying all characteristics of claudin-low tumors including mesenchymal features, undifferentiated traits, and stem-cell-like properties. EMT might thus drive the development of claudin-low tumors by exhibiting a dual role in cell transformation and dedifferentiation. In other terms, the claudin-low tumor subtype of breast cancers might thus constitute a first example of human adult malignancies driven by aberrant reactivation of an embryonic transdifferentiation program. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4813. doi:1538-7445.AM2012-4813