Glioblastoma (GBM), a rare, highly aggressive and chemoresistant brain cancer, exhibits profound metabolic plasticity that relies, in part, on aberrant transforming growth factor-β (TGF-β) signaling. Show more
Glioblastoma (GBM), a rare, highly aggressive and chemoresistant brain cancer, exhibits profound metabolic plasticity that relies, in part, on aberrant transforming growth factor-β (TGF-β) signaling. Such plasticity was recently associated with TGF-β-regulated apoptosis and autophagy. Here, we questioned whether TGF-β-regulated apoptotic/autophagic phenotypes are recapitulated in a preclinical in vitro 3D spheroid culture model of human U87 GBM-derived cells, and how metabolic alterations affect such phenotypes. 3D U87 spheroids were cultured using the hanging drop method. Western blotting was used to assess protein expression, while RT-qPCR was used to assess gene expression levels. 3D spheroids exhibited decreased AKT phosphorylation, and increased TGF-β, fibronectin, and Smad2 phosphorylation, indicative of both cell death signaling and epithelial-mesenchymal transition molecular signatures. 2-Deoxy- 3D spheroids require ATP and a TGF-β/TGF-βR1 autocrine signaling axis to recapitulate the apoptosis/autophagy phenotypes. Combining glycolysis inhibition with TGF-β signaling inhibition could offer a promising therapeutic strategy for this rare and lethal brain cancer. Show less
During obesity, the excessive accumulation of fat in tissue promotes dysregulated hormonal and cytokine homeostasis that triggers chronic inflammation, which is, in part, associated with an increased Show more
During obesity, the excessive accumulation of fat in tissue promotes dysregulated hormonal and cytokine homeostasis that triggers chronic inflammation, which is, in part, associated with an increased incidence of some cancers. This protumoral inflammatory environment is further exacerbated through the secretome of mature adipocytes, which promotes tumor angiogenesis. Emerging studies suggest that human adipocyte-derived mesenchymal stromal/stem cells (ADMSCs) may contribute to a complementary process supporting local angiogenesis termed vasculogenic mimicry (VM). The molecular mechanisms linking ADMSCs to VM and inflammation remain poorly understood. ADMSC 3D capillary-like structures were generated upon seeding on Cultrex. Structure analysis was performed using WIMASIS. Total RNA was extracted using TRIzol and RT-qPCR was performed to assess gene expression or screen RT Our findings revealed that in vitro priming of ADMSCs with Cultrex led to the formation of 3D capillary-like structures and the acquisition of an inflammatory molecular signature. VM-derived ADMSCs share a common proinflammatory molecular signature similar to that induced in 2D ADMSC monolayers by tumor necrosis factor (TNF)-alpha and are characterized by upregulated expression of COX2, CCL2, CCL5, CXCL5, CXCL8, IL-6, SNAI1, and MMP9. Interestingly, pharmacological inhibition or gene silencing of the JAK2/STAT3 signaling pathway reduced chemotactic cell migration, in vitro VM and the expression of proinflammatory and invasive biomarkers. Overall, we provide novel evidence that inhibiting JAK2/STAT3-regulated VM can also alter the acquisition of a proinflammatory signature and prevent the contribution of ADMSCs to alternative tumor neovascularization processes. Show less