L’émission X associée à l’accrétion sur un objet compact présenter une important variabilit photométrique et spectroscopique. Quand l’accréteur est en orbite autour d’une étoile Supergéante, il capture une fraction du vent stellaire supersonique qui forme des chocs dans son voisinage. L’amplitude et la stabilité de cette focalisation gravitationnelle conditionnent le taux d’accrétion de masse responsable, in fine, de la luminosité X des Binaires X Supergéantes (SgXB). La capacité de ce flot à faible moment angulaire à former un disque susceptible de présenter des instabilités est en jeu.Grâce à des setups numériques sophistiqués, nous caractérisons la structure du flot de Bondi- Hoyle-Lyttleton sur un objet compact, depuis le choc jusqu’au voisinage de l’accréteur, typiquement 5 ordres de grandeur plus petit. L’évolution du choc détaché qui se forme autour de l’accréteur (structure transverse, angle d’ouverture, stabilité, profil de température) avec le nombre de Mach est détaillé. La fiabilité de ces simulations basées sur le code hautes performances MPI-AMRVAC est étayée par la topologie de la surface sonique, en accord avec le attentes théoriques.Nous développons un modèle synthétique de transfert de masse dans les SgXB qui couple le lancement du vent, les paramètres stellaires, l’évolution orbital du flot et l’accrétion. Nous montrons que la forme du flot est entièrement détermimée par les facteur de remplissage et d’Eddington, le rapport de masse et le multiplieur de force alpha. Avec les paramètres d’échelle, nous pouvons en déduire, eg, la luminosité X, le processus d’accrétion et le cisaillement du flot. / X-ray emission associated to accretion onto compact objects displays important levels of photometric and spectroscopic time-variability. When the accretor orbits a Supergiant star, it captures a fraction of the supersonic radiatively-driven wind which forms shocks in its vicinity. The amplitude and stability of this gravitational beaming of the flow conditions the mass accretion rate responsible, in fine, for the X-ray luminosity of those Supergiant X-ray Binaries (SgXB). The capacity of this low angular momentum inflow to form a disc susceptible to be the stage of instabilities remains at stake.Using state-of-the-art numerical setups, we characterize the structure of a Bondi-Hoyle- Lyttleton flow onto a compact object, from the shock down to the vicinity of the accretor, typically five orders of magnitude smaller. The evolution of the bow shock which forms around the accretor (transverse structure, opening angle, stability, temperature profile...) with the Mach number of the flow is detailed. The robustness of those simulations based on the High Performance Computing MPI-AMRVAC code is supported by the topology of the inner sonic surface, consistent with theoretical expectations.We develop a synthetic model of mass transfer in SgXB which couples the launching of the wind the stellar parameters, the orbital evolution of the streamlines and the accretion process. We show that the shape of the permanent flow is entirely determined by the filling and Eddington factor, the mass ratio and the alpha force multiplier. Provided scales are known, we can trace back, eg, the X-ray luminosity, the accretion mechanism (stream or wind-dominated) and the shearing of the inflow.

Abstract Desmoglein 3 (Dsg3) is an adhesion receptor in desmosomes, but relatively little is known about its role in cancer. In this study, the function of Dsg3 was investigated in oral squamous cell carcinoma (SCC) cell lines in vitro using locally established human leiomyoma tumor microenvironment (TME) matrices. Since Dsg3 has been identified as a key regulator in cell adhesion, we hypothesized that it may play a role in oral SCC cells adhesion and motility. Thus, one aim of the study was to explore this hypothesis by both gain and loss of function methods in four human buccal mucosa SCC SqCC/Y1 cell lines: transduction of vector control (Ct), full-length (FL) or two different C-terminally truncated Dsg3 mutants (Δ238 and Δ560). Live cell imaging was performed for 2D migration and 3D sandwich, alongside other assays. In 3D sandwich, we tested the effects of the monoclonal antibody, AK23, targeting the extracellular domain of Dsg3 in SqCC/Y1 cells. Our results showed that loss of Dsg3 disrupted cell adhesion and protein expression. In 2D assays, FL and Dsg3 mutants migrated faster with higher accumulated distances than Ct. In contrast with 2D, mutants showed accelerated invasion over the Ct in 3D models. The AK23 antibody inhibited only the invasion of FL cells. The TME in vivo consists of cellular and matrix elements playing a leading role in carcinoma progression. To study carcinoma cells invasion in vitro, mouse Matrigel® and rat type 1 collagen are the most commonly used matrices in 3D models. Since they are non-human in origin, they do not perfectly mimic human TME. To address this, we have developed a solid organotypic myoma disc model derived from human uterus leiomyoma tumor. Here, we introduce a novel Myogel, prepared from leiomyoma similar to Matrigel®. We validated Myogel for cell-TME interactions in 3D models, using SqCC/Y1 and HSC-3 cell lines. Compared with Matrigel® and type I collagen, oral SCC cell lines invaded more efficiently in Myogel containing matrices. This study describes promising 3D models using human TME mimicking Myogel which is suitable to analyze oral SCC cells both in carcinoma monocultures and in co-cultures, such as with TME fibroblasts. We also introduce a possible novel therapeutic target against Dsg3 to suppress cancer cell invasion. / Tiivistelmä Desmogleiini 3 (Dsg3) on desmosomien adheesioreseptori, jonka merkityksestä syövässä tiedetään vähän. Koska Dsg3 on tärkeä epiteelisolujen välisissä liitoksissa, oletimme sillä olevan vaikutusta myös suun karsinoomasolujen tarttumisessa ja niiden liikkuvuudessa. Testasimme hypoteesiamme muuttamalla Dsg3:n toimintaa ihmisen posken karsinoomasolulinjassa SqCC/Y1, josta oli aiemmin valmistettu neljä erilaista muunnosta: tyhjän vektorin sisältävä kontrollisolulinja (Ct), kokopitkää Dsg3 tuottava solulinja (FL), sekä kaksi Dsg3 C-päästä lyhennettyä mutanttisolulinjaa (Δ238 ja Δ560). Immunofluoresenssi-menetelmää käyttäen analysoimme solulinjoissamme solujen välisiä liitoksia. Lisäksi mittasimme solujen liikkeitä 2D-migraatio- ja 3D-sandwich-kokeissa. Testasimme myös Dsg3:n solunulkoista osaa tunnistavan monoklonaalisen vasta-aineen (AK23) vaikutusta solujen invaasioon. Osoitimme, että Dsg3:n rakenteen muuttaminen ja toiminnan estyminen häiritsi solujen tarttumista. 2D-kokeissa sekä FL että mutanttilinjat (Δ238 ja Δ560) migroivat kontrollisoluja nopeammin ja pidemmälle, mutta 3D-kokeissa vain mutanttilinjat invasoituivat kontrollisoluja tehokkaammin. AK23-vasta-aine esti vain FL-solujen invaasiota. Syöpäsolujen 3D-invaasiota mittaavissa kokeissa käytetään yleensä hiiren kasvaimesta valmistettua kaupallista Matrigeeliä® tai rotan kudoksista eristettyä tyypin I kollageenia. Tutkimusryhmämme on jo aiemmin kehittänyt organotyyppisen myoomamallin, jossa valmistamme myoomakudosnapit ihmisen kohdun leiomyoomakasvaimista. Tässä työssä valmistimme leiomyoomasta Myogeelia, vertasimme sitä Matrigeeliin®, sekä tutkimme tarkemmin Myogeeli-valmisteen soveltuvuutta 3D-tutkimuksiin. Totesimme, että kielen (HSC-3) ja posken (SqCC/Y1) karsinoomasolut invasoituivat tehokkaimmin Myogeeli-pitoisissa matrikseissa kuin Matrigeeliä® tai kollageeniä sisältävissä kasvatusalustoissa. Tutkimustulostemme perusteella Myogeeli-pohjaiset 3D-mallit soveltuvat hyvin sekä syöpäsolulinjojen invaasiotutkimuksiin että yhteisviljelmiin, joissa syöpäsoluja viljellään yhdessä syöpäkasvaimen ympärillä olevien solujen, kuten fibroblastien, kanssa.

Apoptosis-induced proliferation (AiP) is a compensatory mechanism to maintain tissue size and morphology following unexpected cell loss during normal development, and may also be a contributing factor to cancer growth and drug resistance. In apoptotic cells, caspase-initiated signaling cascades lead to the downstream production of mitogenic factors and the proliferation of neighboring surviving cells. In epithelial Drosophila tissues, the Caspase-9 homolog Dronc drives AiP via activation of Jun N-terminal kinase (JNK); however, the specific mechanisms of JNK activation remain unknown. Using a model of sustained AiP that produces a hyperplastic phenotype in Drosophila eye and head tissue, I have found that caspase-induced activation of JNK during AiP depends on extracellular reactive oxygen species (ROS) generated by the NADPH oxidase Duox. I found these ROS are produced early in the death-regeneration process by undifferentiated epithelial cells that have initiated the apoptotic cascade. I also found that reduction of these ROS by mis-expression of extracellular catalases was sufficient to reduce the frequency of overgrowth associated with our model of AiP. I further observed that extracellular ROS attract and activate Drosophila macrophages (hemocytes), which may in turn trigger JNK activity in epithelial cells by signaling through the TNF receptor Grindelwald. We propose that signaling back and forth between epithelial cells and hemocytes by extracellular ROS and Grindelwald drives compensatory proliferation within the epithelium, and that in cases of persistent signaling, such as in our sustained model of AiP, hemocytes play a tumor promoting role, driving overgrowth.