Oncogene-induced senescence functions to limit tumor development. However, a complete understanding of the signals that trigger this type of senescence is currently lacking. We found that mutations affecting NF1, Raf, and Ras induce a global negative feedback response that potently suppresses Ras and/or its effectors. Moreover, these signals promote senescence by inhibiting the Ras/PI3K pathway, which can impact the senescence machinery through HDM2 and FOXO. This negative feedback program is regulated in part by RasGEFs, Sprouty proteins, RasGAPs, and MKPs. Moreover, these signals function in vivo in benign human tumors. Thus, the ultimate response to the aberrant activation of the Ras pathway is a multifaceted negative feedback signaling network that terminates the oncogenic signal and participates in the senescence response.
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.
BackgroundThe p53 protein is expressed as multiple isoforms that differ in their N- and C-terminus due to alternative splicing, promoter or codon initiation usage. Δ40p53 lacks the first 39 residues containing the main transcriptional activation domain, resulting from initiation of translation at AUG +40 in fully spliced p53 mRNA or in a specific variant mRNA retaining intron 2. Overexpression of Δ40p53 antagonizes wild-type p53 in vitro. However, animal models of Δ40p53 in mouse or Zebrafish have shown complex phenotypes suggestive of p53-dependent growth suppressive effects.MethodsWe have co-transfected expression vectors for p53 and Δ40p53 in p53-null cell lines Saos-2 and H1299 to show that Δ40p53 forms mixed oligomers with p53 that bind to DNA and modulate the transcription of a generic p53-dependent reporter gene.ResultsIn H1299 cells, co-expression of the two proteins induced a decrease in transcription with amplitude that depended upon the predicted composition of the hetero-tetramer. In Saos-2, a paradoxical effect was observed, with a small increase in activity for hetero-tetramers predicted to contain 1 or 2 monomers of Δ40p53 and a decrease at higher Δ40p53/p53 ratios. In this cell line, co-transfection of Δ40p53 prevented Hdm2-mediated degradation of p53.ConclusionΔ40p53 modulates transcriptional activity by interfering with the binding of Hdm2 to hetero-tetramers containing both Δ40p53 and p53. These results provide a basis for growth suppressive effects in animal models co-expressing roughly similar levels of p53 and Δ40p53.
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
archive tumor and ctDNA samples was 97% (n = 125). EZH2 mutation detection rates in archive tumor were 9% in DLBCL and 21% in FL, consistent with previous reports. MT's in EZH2 or MYD88 in WT EZH2 pts were associated with response (P < .1) whereas MT's in HIST1H1E or MYC (P < .08) were associated with nonresponse. Pts matching a multi gene predictor consisting of WT MYC and/or HIST1H1E but with MT STAT6 and/or MYD88 in archive tumor had ORR = 53% (10/19) whereas pts who did not match this profile had ORR = 16% (12/73) indicating potential for these genes to predict response to tazemetostat. of the CpGs analysed. Considering a false-discovery rate of q < 0.05, this result indicates that PCNSL and DLBCL are strongly similar in their DNA methylation profiles and, if at all, differ only marginally.To address whether these minor, purely statistical differences in DNA methylation between PCNSL and DLBCL translate into biological implications, we further analysed these 2226 loci. First, we performed an unsupervised cluster analysis of the 26 PCNSL for these loci that did not separate them into different groups. Next, we investigated these 2226 loci by evaluating whether they are enriched in functional methylation modules previously described in normal B-cell differentiation. Remarkably, on a global level, they were significantly depleted for those CpGs involved in normal B-cell differentiation indicating that the differentially methylated CpGs are not closely associated to B-cell function. Moreover, the genes linked to the 2226 CpGs are enriched in polycomb targets in stem cells, which is a characteristic feature of CpG DNA methylation signatures linked to cancer and aging in general rather than being specific for a tumor subtype. Conclusions Conclusion:In conclusion, the detailed analyses of the 2226 CpGs differentially methylated between PCNSL and DLBCL with regard to biological meaning suggests a rather unspecific cancer effect rather than a specific role in B-cell lymphomagenesis. Hence, our findings support those of our previous study and indicate that the landscape of DNA methylation of PCNSL is similar to DLBCL.
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