Cancer cells, on your histone marks, get SETDB1, silence retrotransposons, and go!

Cancer cells thrive on genetic and epigenetic changes that confer a selective advantage but also need strategies to avoid immune recognition. In this issue, Cuellar et al. (2017. J. Cell Biol https://doi.org/10.1083/jcb.201612160) find that the histone methyltransferase SETDB1 enables acute myeloid leukemia cells to evade sensing of retrotransposons by innate immune receptors

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy

Immunofibroblasts are pivotal drivers of tertiary lymphoid structure formation and local pathology.

Resident fibroblasts at sites of infection, chronic inflammation, or cancer undergo phenotypic and functional changes to support leukocyte migration and, in some cases, aggregation into tertiary lymphoid structures (TLS). The molecular programming that shapes these changes and the functional requirements of this population in TLS development are unclear. Here, we demonstrate that external triggers at mucosal sites are able to induce the progressive differentiation of a population of podoplanin (pdpn)-positive stromal cells into a network of immunofibroblasts that are able to support the earliest phases of TLS establishment. This program of events, that precedes lymphocyte infiltration in the tissue, is mediated by paracrine and autocrine signals mainly regulated by IL13. This initial fibroblast network is expanded and stabilized, once lymphocytes are recruited, by the local production of the cytokines IL22 and lymphotoxin. Interfering with this regulated program of events or depleting the immunofibroblasts in vivo results in abrogation of local pathology, demonstrating the functional role of immunofibroblasts in supporting TLS maintenance in the tissue and suggesting novel therapeutic targets in TLS-associated diseases

Mutant-IDH1-dependent chromatin state reprogramming, reversibility, and persistence

Mutations in IDH1 and IDH2 (encoding isocitrate dehydrogenase 1 and 2) drive the development of gliomas and other human malignancies. Mutant IDH1 induces epigenetic changes that promote tumorigenesis, but the scale and reversibility of these changes are unknown. Here, using human astrocyte and glioma tumorsphere systems, we generate a large-scale atlas of mutant-IDH1-induced epigenomic reprogramming. We characterize the reversibility of the alterations in DNA methylation, the histone landscape, and transcriptional reprogramming that occur following IDH1 mutation. We discover genome-wide coordinate changes in the localization and intensity of multiple histone marks and chromatin states. Mutant IDH1 establishes a CD24+ population with a proliferative advantage and stem-like transcriptional features. Strikingly, prolonged exposure to mutant IDH1 results in irreversible genomic and epigenetic alterations. Together, these observations provide unprecedented high-resolution molecular portraits of mutant-IDH1-dependent epigenomic reprogramming. These findings have substantial implications for understanding of mutant IDH function and for optimizing therapeutic approaches to targeting IDH-mutant tumors

Study and simulation of helicopters main gearboxes noises

La boîte de transmission principale (BTP) est une des principales sources dubruit perçu dans les cabines d’hélicoptères et pénalise fortement le confort acoustique deséquipages et passagers. Afin de réduire l’impact de cette source, les phénomènes acoustiqueset vibratoires mis en jeu par les boîtes de transmission à engrenages doivent être compris etsimulés durant les phases de développement. De cette façon, le comportementvibroacoustique des BTP pourra être amélioré dès la conception, réduisant ainsi le coût, lamasse et les difficultés d’intégration des solutions d’insonorisation. Ce travail présente lesBTP d’hélicoptères ainsi que le bruit qu’elles génèrent. Il présente également nosdéveloppements concernant la modélisation du comportement dynamique des BTP afin d’encalculer le bruit. Nous avons développé un code éléments finis permettant d’effectuer desétudes paramétriques afin d’ajuster le design des boîtes de transmission lors des phases dedéveloppement. Notre modèle est capable de calculer les efforts dynamiques aux paliers detransmissions composées de plusieurs engrenages cylindriques et spiro-coniques. Enfin, nousanalysons des mesures acoustiques et vibratoires effectuées autour de deux BTP pourplusieurs conditions de couple et vitesse. Ces mesures nous permettent de mieux comprendrele comportement vibroacoustique des BTP et de confirmer certaines tendances observées avecnotre modèleMain gearbox (MGB) is one of the main noise sources in helicopter cabinsand it strongly penalizes acoustic comfort of crews and passengers. In order to reduce theimpact of this source, acoustic and vibration mechanisms of gearboxes have to be understoodand simulated during the development phases. By this way, MGB vibroacoustic behaviourcould be improved by design, thus reducing cost, additional weight and integration difficultiesof sound-proofing solutions. This work presents helicopters MGB and the noise they generate.It also presents our developments regarding the modelling of MGB dynamic behaviour fornoise computation. We have developed a finite elements code allowing to conduct parametricstudies to tune the gearboxes design in early development phases. Our model is able tocompute dynamic loads on bearings of any transmission composed of several cylindrical andspiral bevel gears. At last, we analyse acoustic and vibration measurements done around twoMGB for several conditions of torque and speed. These measurements allow to betterunderstand MGB vibroacoustic behaviour and to confirm some trends observed with ourmode