TWIST1 a New Determinant of Epithelial to Mesenchymal Transition in EGFR Mutated Lung Adenocarcinoma

Metastasis is a multistep process and the main cause of mortality in lung cancer patients. We previously showed that EGFR mutations were associated with a copy number gain at a locus encompassing the TWIST1 gene on chromosome 7. TWIST1 is a highly conserved developmental gene involved in embryogenesis that may be reactivated in cancers promoting both malignant conversion and cancer progression through an epithelial to mesenchymal transition (EMT). The aim of this study was to investigate the possible implication of TWIST1 reactivation on the acquisition of a mesenchymal phenotype in EGFR mutated lung cancer. We studied a series of consecutive lung adenocarcinoma from Caucasian non-smokers for which surgical frozen samples were available (n = 33) and showed that TWIST1 expression was linked to EGFR mutations (P<0.001), to low CDH1 expression (P<0.05) and low disease free survival (P = 0.044). To validate that TWIST1 is a driver of EMT in EGFR mutated lung cancer, we used five human lung cancer cell lines and demonstrated that EMT and the associated cell mobility were dependent upon TWIST1 expression in cells with EGFR mutation. Moreover a decrease of EGFR pathway stimulation through EGF retrieval or an inhibition of TWIST1 expression by small RNA technology reversed the phenomenon. Collectively, our in vivo and in vitro findings support that TWIST1 collaborates with the EGF pathway in promoting EMT in EGFR mutated lung adenocarcinoma and that large series of EGFR mutated lung cancer patients are needed to further define the prognostic role of TWIST1 reactivation in this subgroup

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

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

GH deficiency status combined with GH receptor polymorphism affects response to GH in children.

Meta-analysis has shown a modest improvement in first-year growth response to recombinant human GH (r-hGH) for carriers of the exon 3-deleted GH receptor (GHRd3) polymorphism but with significant interstudy variability. The associations between GHRd3 and growth response to r-hGH over 3 years in relation to severity of GH deficiency (GHD) were investigated in patients from 14 countries. Treatment-naı¨ve pre-pubertal children with GHD were enrolled from the PREDICT studies (NCT00256126 and NCT00699855), categorized by peak GH level (peak GH) during provocation test: %4 mg/l (severe GHD; nZ45) andO4 to!10 mg/l mild GHD; nZ49) and genotyped for the GHRd3 polymorphism (full length (fl/fl, fl/d3, d3/d3). Gene expression (GE) profiles were characterized at baseline. Changes in growth (height (cm) and SDS) over 3 years were measured. There was a dichotomous influence of GHRd3 polymorphism on response to r-hGH, dependent on peak GH level. GH peak level (higher vs lower) and GHRd3 (fl/fl vs d3 carriers) combined status was associated with height change over 3 years (P!0.05). GHRd3 carriers with lower peak GH had lower growth than subjects with fl/fl (median difference after 3 years K3.3 cm; K0.3 SDS). Conversely, GHRd3 carriers with higher peak GH had better growth (C2.7 cm; C0.2 SDS). Similar patterns were observed for GH-dependent biomarkers. GE profiles were significantly different between the groups, indicating that the interaction between GH status and GHRd3 carriage can be identified at a transcriptomic level. This study demonstrates that responses to r-hGH depend on the interaction between GHD severity and GHRd3 carriage

Organ-wide and ploidy-dependent regulations both contribute to cell size determination: evidence from a computational model of tomato fruit

The development of a new organ is the result of coordinated events of cell division and expansion, in strong interaction with each other. This paper presents a dynamic model of tomato fruit development that includes cells division, endoreduplication and expansion processes. The model is used to investigate the interaction among these developmental processes, in the perspective of a neo-cellular theory. In particular, different control schemes (either cell-autonomous or organ-controlled) are tested and results compared to observed data from two contrasted genotypes. The model shows that a pure cell-autonomous control fails to reproduce the observed cell size distribution, and an organ-wide control is required in order to get realistic cell sizes. The model also supports the role of endoreduplication as an important determinant of the final cell size and suggests a possible interaction through carbon allocation and metabolism

Assessment of the water stress effects on peach fruit quality and size using a fruit tree model, QualiTree

Low water availability has increased the use of regulated deficit irrigation strategies in fruit orchards.However, these water restrictions may have implications on fruit growth and quality. The current paperassesses the suitability of an existing fruit tree model (QualiTree) for describing the effects of water stresson peach fruit growth and quality. The model was parameterised and calibrated for a mid-late maturingpeach cultivar (‘Catherine’). Mean and variability over time of fruit and vegetative growth were consistentwith observed data on trees submitted to full irrigation or to regulated deficit irrigation. The relative rootmean square errors of the model for growth ranged between 0.09 and 0.31.Sugar contents in fruit flesh were fairly well simulated, except for sucrose, which was overestimated.The relative root mean square errors of the model ranged from 0.01 to 0.40 for fructose; from 0.04 to0.05 for glucose; from 0.21 to 0.41 for sucrose and from 0.09 to 0.28 for sorbitol. Water stress reducedleafy shoot growth up to 23% and fruit final size up to 49% when compared to the well-watered control.However, sugar contents in the flesh increased with water stress, up to 70% in the case of glucose. Sim-ulations showed that a severe water stress during stage III of fruit development decreased fruit sizes by22%, when compared to the control, whereas it enhanced sugar accumulation in the fruit flesh, up to 70%in the case of glucose and fructose. Therefore, these simulations showed that QualiTree might be usefulin the design of innovative horticultural practices

Coupling the functional-structural plant models MAppleT and QualiTree to simulate carbon allocation and growth variability within Apple tree

International audiencePlant growth highly depends on the carbon allocation which results from combined effects of environment, horticultural practices and management. QualiTree had demonstrated to be a useful model to simulate carbon allocation within the tree structure for peach trees submitted to contrasted cultivation practices (crop load) and soil water availability. The objective of this study was to adapt QualiTree to apple trees to simulate carbon economy and growth dynamics as well as variability within tree. Peach tree architecture is managed by standardized pruning practices whereas apple tree pruning is more tailored this leading to a greater variability of architecture. To take this variability into account, we used MAppleT to generate random tree architectures corresponding to the ‘Fuji’ cultivar. The architecture generated by MAppleT was saved into a Multiscale Tree Graph (MTG) and included information on all shoots and fruits location as well as their initial weights. This information was then used as input for QualiTree. Furthermore, based on the observed growth capacity of apple tree annual shoots, we modified QualiTree to take into account three different classes of shoots (long, medium and short) that are characterized by different growth rate and duration. The light interception sub-model, based on a turbid medium hypothesis, was also modified to allow the usage of user-defined ellipsoids to better represent the shape of apple trees. To calibrate the model, different parameter combinations of initial relative organ/shoot growth rate, maximum shoot biomass and duration of growth were tested to simulate adequately the variability of fruit and leafy shoot growth. The simulations were compared to previous 3-dimensional digitized measurements performed on ‘Fuji’ apple trees. Finally, the new version of QualiTree was used to simulate the impact of water stress, tree architecture and fruit load effect on organ growth dynamics and variability within tree structure. This modeling approach coupling MAppleT and QualiTree would help deeper understanding on complex interaction between growth, architecture and cultivation practices. To reach this objective, further works are needed to integrate into MAppleT retroaction loops between carbon allocation and plant architecture establishment

Coupling epidemiological and tree growth models to control fungal diseases spread in fruit orchards

International audienceAgronomic practices can alter plant susceptibility to diseases and represent a promising alternative to the use of pesticides. Yet, they also alter crop quality and quantity so that the evaluation of their efficacy is not straightforward. Here we couple a compartmental epidemiological model for brown rot diffusion in fruit orchards with a fruit-tree growth model explicitly considering the role of agronomic practices over fruit quality. The new modelling framework permits us to evaluate, in terms of quantity and quality of the fruit production, management scenarios characterized by different levels of regulated deficit irrigation and crop load. Our results suggest that a moderate water stress in the final weeks of fruit development and a moderate fruit load provide effective control on the brown rot spreading, and eventually guarantee monetary returns similar to those that would be obtained in the absence of the disease