TAZ role in lung cancer: resistance to BET inhibitors and functional interaction with lncRNA

Despite extensive research and introduction of innovative therapy, lung cancer prognosis remains poor, with a five years survival of only 17%. The success of pharmacological treatment is often impaired by drug resistance. Thus, the characterization of response mechanisms to anti-cancer compounds and of the molecular mechanisms supporting lung cancer aggressiveness are crucial for patient’s management. In the first part of this thesis, we characterized the molecular mechanism behind resistance of lung cancer cells to the Inhibitors of the Bromodomain and Extraterminal domain containing Proteins (BETi). Through a CRISPR/Cas9 screening we identified three Hippo Pathway members, LATS2, TAOK1 and NF2 as genes implicated in susceptibility to BETi. These genes confer sensitivity to BETi inhibiting TAZ activity. Conversely, TAZ overexpression increases resistance to BETi. We also displayed that BETi downregulate both YAP, TAZ and TEADs expression in several cancer cell lines, implying a novel BETi-dependent cytotoxic mechanism. In the second part of this work, we attempted to characterize the crosstalk between the TAZ gene and its cognate antisense long-non coding RNA (lncRNA) TAZ-AS202 in lung tumorigenesis. As for TAZ downregulation, TAZ-AS202 silencing impairs NSCLC cells proliferation, migration and invasion, suggesting a pro-tumorigenic function for this lncRNA during lung tumorigenesis. TAZ-AS202 regulates TAZ target genes without altering TAZ expression or localization. This finding implies an uncovered functional cooperation between TAZ and TAZ-AS202. Moreover, we found that the EPH-ephrin signaling receptor EPHB2 is a downstream effector affected by both TAZ and TAZ-AS202 silencing. EPHB2 downregulation significantly attenuates cells proliferation, migration and invasion, suggesting that, at least in part, TAZ-AS202 and TAZ pro-oncogenic activity depends on EPH-ephrin signaling final deregulation. Finally, we started to dissect the mechanism underlying the TAZ-AS202 regulatory activity on EPHB2 in lung cancer, which may involve the existence of an intermediate transcription factor and is the object of our ongoing research.

Ship performance modelling for least-CO2 emission routes

Decarbonization of maritime transport requires immediate action. In the short term, ship weather routing can provide greenhouse gas emission reductions, even for existing ships and without retrofitting them. Weather routing is based on making optimal use of both envi- ronmental information and knowledge about vessel seakeeping and performance. Combining them at a state-of-the-art level and making use of path planning in realistic conditions can be challenging. To address these topics in an open-source framework, this thesis led to the development of a new module called bateau , and to its combination with the ship routing model VISIR. bateau includes both hull geometry and propulsion modelling for various vessel types. It has two objectives: to predict the sustained speed in a seaway and to estimate the CO2 emission rate during the voyage. Various semi-empirical approaches were used in bateau to predict the ship hydro- and aerodynamical resistance in both head and oblique seas. Assuming that the ship sails at a constant engine load, the involuntary speed loss due to waves was estimated. This thesis also attempted to clarify the role played by the actual representation of the sea state. In particular, the influence of the wave steepness parameter was assessed. For dealing with ships with a greater superstructure, the wind added resistance was also estimated. Numerical experiments via bateau were conducted for both a medium and a large-size container ships, a bulk-carrier, and a tanker. The simulations of optimal routes were carried out for a feeder containership during voyages in the North Indian Ocean and in the South China Sea. Least-CO2 routes were compared to the least-distance ones, assessing the relative CO2 savings. Analysis fields from the Copernicus Marine Service were used in the numerical experiments.