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Transforming growth factor-beta (TGF-β) is a pleiotropic cytokine with the capability to act as tumour suppressor or tumour promoter depending on the cellular context. TGF-beta receptor type-2 (TGFBR2) is the ligand-binding receptor for all members of the TGF-β family. Data from mouse model experiments demonstrated that loss of Tgfbr2 expression in mammary fibroblasts was linked to tumour initiation and metastasis. Using a randomised tamoxifen trial cohort including in total 564 invasive breast carcinomas, we examined TGFBR2 expression ( n =252) and phosphorylation level of downstream target SMAD2 (pSMAD2) ( n =319) in cancer-associated fibroblasts (CAFs) and assessed links to clinicopathological markers, prognostic and treatment-predictive values. The study revealed that CAF-specific TGFBR2 expression correlated with improved recurrence-free survival. Multivariate analysis confirmed CAF-TGFBR2 to be an independent prognostic marker (multivariate Cox regression, hazard ratio: 0.534, 95% (CI): 0.360–0.793, P =0.002). CAF-specific pSMAD2 levels, however, did not associate with survival outcome. Experimentally, TGF-β signalling in fibroblasts was modulated using a TGF-β ligand and inhibitor or through lentiviral short hairpin RNA-mediated TGFBR2 -specific knockdown. To determine the role of fibroblastic TGF-β pathway on breast cancer cells, we used cell contact-dependent cell growth and clonogenicity assays, which showed that knockdown of TGFBR2 in CAFs resulted in increased cell growth, proliferation and clonogenic survival. Further, in a mouse model transfected CAFs were co-injected with MCF7 and tumour weight and proportion was monitored. We found that mouse xenograft tumours comprising TGFBR2 knockdown fibroblasts were slightly bigger and displayed increased tumour cell capacity. Overall, our data demonstrate that fibroblast-related biomarkers possess clinically relevant information and that fibroblasts confer effects on breast cancer cell growth and survival. Regulation of tumour–stromal cross-talk through fibroblastic TGF-β pathway may depend on fibroblast phenotype, emphasising the importance to characterise tumour microenvironment subtypes.

Substantial progress has been achieved over the last four decades to better understand a deep structure in the Himalayas and Tibet. Nevertheless, the remoteness of this part of the world still considerably limits the use of seismic data. A possible way to overcome this practical restriction partially is to use products from the Earth’s satellite observation systems. Global topographic data are provided by the Shuttle Radar Topography Mission (SRTM). Global gravitational models have been derived from observables delivered by the gravity-dedicated satellite missions, such as the Gravity Recovery and Climate Experiment (GRACE) and the Gravity field and steady-state Ocean Circulation Explorer (GOCE). Optimally, the topographic and gravity data should be combined with available results from tomographic surveys to interpret the lithospheric structure, including also a Moho relief. In this study, we use seismic, gravity, and topographic data to estimate the Moho depth under orogenic structures of the Himalayas and Tibet. The combined Moho model is computed based on solving the Vening Meinesz–Moritz (VMM) inverse problem of isostasy, while incorporating seismic data to constrain the gravimetric solution. The result of the combined gravimetric-seismic data analysis exhibits an anticipated more detailed structure of the Moho geometry when compared to the solution obtained merely from seismic data. This is especially evident over regions with sparse seismic data coverage. The newly-determined combined Moho model of Tibet shows a typical contrast between a thick crustal structure of orogenic formations compared to a thinner crust of continental basins. The Moho depth under most of the Himalayas and the Tibetan Plateau is typically within 60–70 km. The maximum Moho deepening of ~76 km occurs to the south of the Bangong-Nujiang suture under the Lhasa terrane. Local maxima of the Moho depth to ~74 km are also found beneath Taksha at the Karakoram fault. This Moho pattern generally agrees with the findings from existing gravimetric and seismic studies, but some inconsistencies are also identified and discussed in this study.