Modelling TGFbR and Hh pathway regulation of prognostic matrisome molecules in ovarian cancer

In a multi-level ‘deconstruction’ of omental metastases, we previously identified a prognostic matrisome gene expression signature in high-grade serous ovarian cancer (HGSOC) and twelve other malignancies. Here, our aim was to understand how six of these extracellular matrix, ECM, molecules, COL11A1, COMP, FN1, VCAN, CTSB and COL1A1, are up-regulated in cancer. Using biopsies, we identified significant associations between TGFβR activity, Hedgehog signalling and these ECM molecules and then studied the associations in mono-, co- and tri-culture. Activated omental fibroblasts produced more matrix than malignant cells, directed by TGFβR and Hedgehog signalling crosstalk. We ‘reconstructed’ omental metastases in tri-culture of HGSOC cells, omental fibroblasts and adipocytes. This combination was sufficient to generate all six ECM proteins and the matrisome expression signature. TGFβR and Hedgehog inhibitor combinations attenuated fibroblast activation, gel remodelling and ECM remodelling in these models. The tri-culture model reproduces key features of omental metastases and allows study of diseased-associated ECM

Measurements and Modeling of the Interhemispheric Differences of Atmospheric Chlorinated Very Short-Lived Substances

Chlorinated very short-lived substances (Cl-VSLS) are ubiquitous in the troposphere and can contribute to the stratospheric chlorine budget. In this study, we present measurements of atmospheric dichloromethane (CH2Cl2), tetrachloroethene (C2Cl4), chloroform (CHCl3), and 1,2-dichloroethane (1,2-DCA) obtained during the National Aeronautics and Space Administration (NASA) Atmospheric Tomography (ATom) global-scale aircraft mission (2016?2018), and use the Community Earth System Model (CESM) updated with recent chlorine chemistry to further investigate their global tropospheric distribution. The measured global average Cl-VSLS mixing ratios, from 0.2 to 13 km altitude, were 46.6 ppt (CH2Cl2), 9.6 ppt (CHCl3), 7.8 ppt (1,2-DCA), and 0.84 ppt (C2Cl4) measured by the NSF NCAR Trace Organic Analyzer (TOGA) during ATom. Both measurements and model show distinct hemispheric gradients with the mean measured Northern to Southern Hemisphere (NH/SH) ratio of 2 or greater for all four Cl-VSLS. In addition, the TOGA profiles over the NH mid-latitudes showed general enhancements in the Pacific basin compared to the Atlantic basin, with up to ?18 ppt difference for CH2Cl2 in the mid troposphere. We tagged regional source emissions of CH2Cl2 and C2Cl4 in the model and found that Asian emissions dominate the global distributions of these species both at the surface (950 hPa) and at high altitudes (150 hPa). Overall, our results confirm relatively high mixing ratios of Cl-VSLS in the UTLS region and show that the CESM model does a reasonable job of simulating their global abundance but we also note the uncertainties with Cl-VSLS emissions and active chlorine sources in the model. These findings will be used to validate future emission inventories and to investigate the fast convective transport of Cl-VSLS to the UTLS region and their impact on stratospheric ozone

Tumour microenvironment 3D-modelling: simplicity to complexity and back again

Tumours are surrounded by a host of noncancerous cells that fulfil both supportive and suppressive roles within the tumour microenvironment (TME). The drive to understand the biology behind each of these components has led to a rapid expansion in the number and use of 3D in vitro models, as researchers find ways to incorporate multiple cell types into physiomimetic configurations. The use and increasing complexity of these models does however demand many considerations. In this review we discuss approaches adopted to recapitulate complex tumour biology in tractable 3D models. We consider how these cell types can be sourced and combined and examine methods for the deconvolution of complex multicellular models into manageable and informative outputs.</p