UPS are a heterogenous group of poorly differentiated tumors. We hypothesized that there is a link between dedifferentiation state of UPS and immune infiltrate and that this relationship relies on ...specific pathways activation and related genomics alterations with potential therapeutic impact. Main objectives were to generate a comprehensive Omics landscape of true UPS and test potential targets for therapeutics approach on cell lines and patient tumour derived mouse xenografts (PDX).
We analysed 135 UPS cases, 25 of which were selected for full exome and RNA sequencing, proteomics profiling conducted by data-independent acquisition mass spectrometry, as well as immune profiling by immunohistochemistry (IHC).
Using unsupervised consensus clustering and hierarchical clustering of RNA-sequencing, we identified two main groups of patients: group A and B, with associated gene clusters. Group A was mainly enriched in genes that play a crucial role in both normal development and stemcellness, notably FGFR2. Group B was strongly enriched in genes involved in immunity. Using proteomics analysis we found two main proteomic groups - PA and PB – that highly correlated with the two main genetic groups - A and B. The proteome group PB, associated with the immune-high group B, was significantly enriched in immune response pathways, whereas the proteome group PA, associated with the immune-low group A, was mainly enriched in MYC targets and epithelial mesenchymal transition pathways. We then further assessed the therapeutic potential of this classification by using in vitro and in vivo PDX models directly derived from patient tumor samples from the molecular profiling study. We showed robust anti-tumor activity of FGFR2 inhibitor JNJ-42756493 and of NEO2734, a first-in-class epigenetic modifier that notably inhibits Bromodomain and Extra-Terminal domain (BET) family and Cyclic AMP response element binding protein (CREB)-binding (CBP) proteins, in models from group A, selectively.
This integrated analysis of UPS allowed the identification of two main entities with distinct molecular features, immune phenotypes, as well as differential sensitivity to specific anti-cancer agents.
The authors.
La Ligue.
All authors have declared no conflicts of interest.
Na+/H+ exchangers (NHE), also called antiporters, are vital transmembrane transporters involved in multiple cellular functions including the regulation of intracellular pH, the control of cell volume ...and transepithelial ion transport. These transporters are highly regulated by a remarkably wide variety of stimuli which can modulate their expression level and activity. Five isoforms of Na+/H+ exchangers have been cloned and characterized to date; they define a new gene family of vertebrate transporters. These isoforms share the same overall structure but exhibit differences with respect to amiloride-sensitivity, cellular localization, kinetic variables, regulation by various stimuli and plasma membrane targeting in polarized epithelial cells. Biochemical techniques and molecular genetics tools provide the means of analyzing these transporters at the molecular level. The purpose of this manuscript is to give an overview of the main features of the Na+/H+ exchangers with emphasis on recent advances in comprehension of the structure-function relationship and regulation mechanisms of the ubiquitous isoform: NHE-1.
Hypertonic activation of NHE1, the ubiquitous Na+/H+ exchanger, plays a central role in cell volume regulation, yet little is known about the underlying mechanism. We probed the osmotic ...responsiveness of full-length and truncated constructs of NHE1 transfected into cells lacking endogenous antiport activity. The hypertonic stimulation of NHE1 was preserved after heterologous transfection of the full-length NHE1 or of constructs truncated at positions 698 or 703. In contrast, mutants truncated at position 635 (delta 635) failed to respond to osmotic challenge. Transfectants (delta 635) behaved as if constitutively activated, having a permanently elevated cytosolic pH (pHi) under isotonic, unstimulated conditions. The delta 635 mutant displayed H+ binding with high affinity and low cooperativity. Constructs delta 582 or delta 566 had a reduced H+ sensitivity and were therefore inactive at resting pHi. Such cells were unresponsive to osmotic stress near physiological pHi but could be activated by shrinking after an acid load. Jointly, these results suggest that the H+ affinity and high cooperativity of the antiporter, earlier attributed to a single "modifier site," can be varied independently and are probably controlled by different regions of the molecule. The data indicate that volume or osmolarity-sensitive site(s) exist between the NH2-terminus and residue 566. This putative volume-sensitive site is therefore different from the site(s) postulated to mediate the stimulatory effects of calcium and growth factors.
Based on aset of length frequency distributions recorded in old experimental traws surveys and recovered from the archives of the Institute of Mazara, this study aims to provide an historical insight ...of the growth, mortality and status of L. cavillone in the Strait of sicily.
The reproductive cycle of the Norway lobster (Nephrops norvegicus) female was investigated to determine the size and age at onset of sexual maturity (SOM), as a baseline to establish the minimum ...catchable size. Samples were gathered in four seasonal (Spring 1986 - Winter 1987) trawl surveys on the Italian side of the Strait of Sicily (Central Mediterranean Sea). The relative frequency of females in different stages of maturation and in berried conditions was observed. According to the ovary stages, gonadal maturation is attained during Spring and Summer; berried animals occur almost exclusively in Summer and Autumn, in about 40% of the sample. Length structure changes slightly by location and by season; recruitment to the gear occurs more or less continuously. Gaussian components appear to be highly overlapped; the resolution of the length frequency distribution values leads to the identification of multiple cohorts, five of which were well represented. The population attains 50% of maturity at 30-32 mm CL, corresponding to an age of 5 years. The mean size of the first Gaussian component from the catch (about 22 mm CL) is well below the estimated size at 50% maturity, suggesting a precocious recruitment to the fishery.
Determining the genetic population structure and intraspecific evolution of species is important for efficient management. Here we investigated 394 sequences of the mtDNA cyt b of the critically ...endangered European eel, Anguilla anguilla. We found 62 different haplotypes, among which 32 novel ones. All those sequences were grouped into 9 haplogroups on the basis of their frequency and links in the haplotype network. Two pairwise comparisons revealed significant genetic differentiation between regions. One comparison indicated small genetic differentiation between the Atlantic Ocean and the North Sea. Another comparison indicated small genetic differentiation between eel samples caught in the Baltic Sea, the Curonian Lagoon and the Gulf of Riga and those captured in the North Sea. The results of the study are in agreement with the recent findings obtained using the mtDNA D-loop region as a molecular marker, indicating that although A. anguilla is considered a panmictic species the genetic structure of its population indicated by mtDNA markers could be characterized as a genetic mosaic.
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