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

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

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Influence of PC superplasticizers on tricalcium silicate hydration.

International audienceThe influence of polycarboxylate superplasticizers with variations of content of anionic groups was studied on pure tricalcium silicate hydration. The hydration in diluted suspension has been investigated by conductimetry, calorimetry, and ionic and total organic carbon analysis of the liquid phase. The tricalcium silicate hydration is always delayed in presence of polycarboxylate superplasticizer. Moreover, the delay can be correlated with the number of carboxylate groups which are on the adsorbed superplasticizer molecules. This effect seems to be due to a decrease of the C3S dissolution rate. Namely the pure C3S dissolution was studied by ICP with or without a carboxylate functionalized latex. A drastic decrease of the C3S dissolution rate was observed in presence of the polycarboxylate functionalized latex and this effect increased with higher hydroxyde calcium concentrations

3D Bioprinting:principles, fantasies and prospects

International audienc

The Italian ITASE Expedition from D85 to M4 (East Antarctica)

As a part of ITASE project (International Trans-Antarctic Scientific Expedition; Mayewski & Goodwin, 1999), between November 2001 and January 2002, the Italian Programma Nazionale di Ricerche in Antartide made a traverse through Adélie, George V, Oates and northern Victoria Lands (Fig. l , Tab. 1). The study aimed to better understand latitudinal and longitudinal gradients along one East-West (D66 - Talos Dome) and two North-South (D85 - D59 and GV7 - Talos Dome - M4) transects, while documenting climatic, atmospheric and surface conditions during the last 200-1000 years in the eastern and north-eastern portions of the Dome C drainage area and in northern Victoria Land. During the 1998/1999 season members of the Italian Antarctic programme made the first traverse from Terra Nova Bay to Dome C (Frezzotti & Flora, 2002). The traverse in the eastern Dome C drainage area took place between 20 November 1998 and 16 January 1999, and covered about 1300 km. The traverse team consisted of eight people: three mechanics and five scientists (four Italians and a French guest). During the 2000/2001 season 69 tons of supplies (fuel, food, snow box, etc.) for the 2001/2002 ITASE campaign were delivered from Cape Prud'homme on the forward legs of the transport traverses (IPEV-PNRA) between Dumont d'Urville and Dome C; the ITASE vehicles were delivered from Dome C to D85 on the return legs of the IPEV-PNRA traverses (Patrice Godon officer in charge of the traverse, personal communication)