Concerted alteration of immune and metabolic homeostasis underlies several inflammation-related pathologies, ranging from metabolic syndrome to infectious diseases. Here, we explored the coordination ...of nucleic acid-dependent inflammatory responses and metabolic homeostasis. We reveal that the STING (stimulator of interferon genes) protein regulates metabolic homeostasis through inhibition of the fatty acid desaturase 2 (FADS2) rate-limiting enzyme in polyunsaturated fatty acid (PUFA) desaturation. STING ablation and agonist-mediated degradation increased FADS2-associated desaturase activity and led to accumulation of PUFA derivatives that drive thermogenesis. STING agonists directly activated FADS2-dependent desaturation, promoting metabolic alterations. PUFAs in turn inhibited STING, thereby regulating antiviral responses and contributing to resolving STING-associated inflammation. Thus, we have unveiled a negative regulatory feedback loop between STING and FADS2 that fine-tunes inflammatory responses. Our results highlight the role of metabolic alterations in human pathologies associated with aberrant STING activation and STING-targeting therapies.
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•STING inhibits FADS2-dependent desaturation of PUFAs and LC-PUFAs•STING activation leads to upregulation of FADS2-associated desaturase activity•STING agonists activate FADS2-dependent PUFA and LC-PUFA desaturation•PUFAs inhibit STING-dependent inflammatory responses
The stimulator of interferon genes (STING) is a central regulator of nucleic acid-associated inflammatory responses. Here, Vila et al. discover that STING regulates polyunsaturated fatty acid (PUFA) metabolism, and in turn, PUFAs inhibit STING-dependent inflammation. This cross-regulation is central to the maintenance of metabolic homeostasis.
The BCL-2-associated athanogene (BAG) family is a multifunctional group of co-chaperones that are evolutionarily conserved from yeast to mammals. In addition to their common BAG domain, these ...proteins contain, in their sequences, many specific domains/motifs required for their various functions in cellular quality control, such as autophagy, apoptosis, and proteasomal degradation of misfolded proteins. The BAG family includes six members (BAG1 to BAG6). Recent studies reported their roles in autophagy and/or mitophagy through interaction with the autophagic machinery (LC3, Beclin 1, P62) or with the PINK1/Parkin signaling pathway. This review describes the mechanisms underlying BAG family member functions in autophagy and mitophagy and the consequences in physiopathology.
Tumor microenvironment is a complex network of epithelial cancer cells and non-transformed stromal cells. Of the many stromal cell types, fibroblasts are the most numerous ones and are traditionally ...viewed as supportive elements of cancer progression. Many studies show that cancer cells engage in active crosstalk with associated fibroblasts in order to obtain key resources, such as growth factors and nutrients. The facets of fibroblast "complicity to murder" in cancer are multiple. However, recent therapeutic attempts aiming at depleting fibroblasts from tumors, perturbed rather simplistic picture. Contrary to the expectations, tumors devoid of fibroblasts accelerated their progression while patients faced poorer outcomes. These studies remind us of the physiologic roles fibroblasts have in maintaining tissue homeostasis even in the presence of cancer. It is becoming increasingly clear that our research focus on advanced tumors has biased our understanding of fibroblast role in tumor biology. The numerous events where the fibroblasts protect the tissue from malignant transformation remain largely unacknowledged, as the tumors are invisible. The present review has the ambition to offer a more balanced view of fibroblasts functions in cancer progression and therapy resistance. We will address the question whether it is possible to synergize the efforts with fibroblasts as the therapeutic concept against tumor progression and therapy resistance.
Pancreatic ductal adenocarcinoma (PDAC) remains a deadly malignancy with no efficient therapy available up‐to‐date. Glycolysis is the main provider of energetic substrates to sustain cancer ...dissemination of PDAC. Accordingly, altering the glycolytic pathway is foreseen as a sound approach to trigger pancreatic cancer regression. Here, we show for the first time that high transforming growth factor beta‐induced (TGFBI) expression in PDAC patients is associated with a poor outcome. We demonstrate that, although usually secreted by stromal cells, PDAC cells synthesize and secrete TGFBI in quantity correlated with their migratory capacity. Mechanistically, we show that TGFBI activates focal adhesion kinase signaling pathway through its binding to integrin αVβ5, leading to a significant enhancement of glycolysis and to the acquisition of an invasive phenotype. Finally, we show that TGFBI silencing significantly inhibits PDAC tumor development in a chick chorioallantoic membrane assay model. Our study highlights TGFBI as an oncogenic extracellular matrix interacting protein that bears the potential to serve as a target for new anti‐PDAC therapeutic strategies.
What's new?
While pancreatic ductal adenocarcinoma (PDAC) continues to have exceedingly low 5‐year survival rates, there is hope that the discovery of reliable biomarkers and therapeutic targets can improve early diagnosis and treatment outcomes. To that end, the authors of this study identify the extracellular matrix protein transforming growth factor beta‐induced (TGFBI) as a promising PDAC target. In PDAC patients, high TGFBI expression was associated with poor outcome. In PDAC cells, tumor aggressiveness was associated with greater TGFBI synthesis and secretion. Mechanistic analyses show that TGFBI activates FAK signaling via integrin αVβ5 binding, enhancing glycolysis and invasiveness in PDAC cells.
Metabolic reprogramming toward aerobic glycolysis unavoidably induces methylglyoxal (MG) formation in cancer cells. MG mediates the glycation of proteins to form advanced glycation end products ...(AGEs). We have recently demonstrated that MG-induced AGEs are a common feature of breast cancer. Little is known regarding the impact of MG-mediated carbonyl stress on tumor progression. Breast tumors with MG stress presented with high nuclear YAP, a key transcriptional co-activator regulating tumor growth and invasion. Elevated MG levels resulted in sustained YAP nuclear localization/activity that could be reverted using Carnosine, a scavenger for MG. MG treatment affected Hsp90 chaperone activity and decreased its binding to LATS1, a key kinase of the Hippo pathway. Cancer cells with high MG stress showed enhanced growth and metastatic potential in vivo. These findings reinforce the cumulative evidence pointing to hyperglycemia as a risk factor for cancer incidence and bring renewed interest in MG scavengers for cancer treatment.
Tumor stroma is composed of many cellular subtypes, of which the most abundant are fibroblasts, macrophages and endothelial cells. During the process of tissue injury, these three cellular subtypes ...must coordinate their activity to efficiently contribute to tissue regeneration. In tumor, this mechanism is hijacked by cancer cells, which rewire the interaction of stromal cells to benefit tumor development. The present review aims at summarizing most relevant information concerning both pro-tumorigenic and anti-tumorigenic actions implicating the three stromal cell subtypes as well as their mutual interactions.
Although stromal cells are generally regarded as tumor-supportive and at will manipulated by cancer cells, several novel studies point at many defaults in cancer cell-mediated stromal reprograming. Indeed, parts of initial tissue-protective and homeostatic functions of the stromal cells remain in place even after tumor development. Both tumor-supportive and tumor-suppressive functions have been well described for macrophages, whereas similar results are emerging for fibroblasts and endothelial cells.
Recent success of immunotherapies have finally brought the long awaited proof that stroma is key for efficient tumor targeting. However, a better understanding of paracrine stromal interactions is needed in order to encourage drug development not only aiming at disruption of tumor-supportive communication but also re-enforcing, existing, tumor-suppressive mechanisms.
Stromal Modulators of TGF-β in Cancer Costanza, Brunella; Umelo, Ijeoma Adaku; Bellier, Justine ...
Journal of clinical medicine,
01/2017, Letnik:
6, Številka:
1
Journal Article, Web Resource
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Transforming growth factor-β (TGF-β) is an intriguing cytokine exhibiting dual activities in malignant disease. It is an important mediator of cancer invasion, metastasis and angiogenesis, on the one ...hand, while it exhibits anti-tumor functions on the other hand. Elucidating the precise role of TGF-β in malignant development and progression requires a better understanding of the molecular mechanisms involved in its tumor suppressor to tumor promoter switch. One important aspect of TGF-β function is its interaction with proteins within the tumor microenvironment. Several stromal proteins have the natural ability to interact and modulate TGF-β function. Understanding the complex interplay between the TGF-β signaling network and these stromal proteins may provide greater insight into the development of novel therapeutic strategies that target the TGF-β axis. The present review highlights our present understanding of how stroma modulates TGF-β activity in human cancers.
Breast cancer is a leading malignancy affecting the female population worldwide. Most morbidity is caused by metastases that remain incurable to date. TGF-β1 has been identified as a key driving ...force behind metastatic breast cancer, with promising therapeutic implications.
Employing immunohistochemistry (IHC) analysis, we report, to our knowledge for the first time, that asporin is overexpressed in the stroma of most human breast cancers and is not expressed in normal breast tissue. In vitro, asporin is secreted by breast fibroblasts upon exposure to conditioned medium from some but not all human breast cancer cells. While hormone receptor (HR) positive cells cause strong asporin expression, triple-negative breast cancer (TNBC) cells suppress it. Further, our findings show that soluble IL-1β, secreted by TNBC cells, is responsible for inhibiting asporin in normal and cancer-associated fibroblasts. Using recombinant protein, as well as a synthetic peptide fragment, we demonstrate the ability of asporin to inhibit TGF-β1-mediated SMAD2 phosphorylation, epithelial to mesenchymal transition, and stemness in breast cancer cells. In two in vivo murine models of TNBC, we observed that tumors expressing asporin exhibit significantly reduced growth (2-fold; p = 0.01) and metastatic properties (3-fold; p = 0.045). A retrospective IHC study performed on human breast carcinoma (n = 180) demonstrates that asporin expression is lowest in TNBC and HER2+ tumors, while HR+ tumors have significantly higher asporin expression (4-fold; p = 0.001). Assessment of asporin expression and patient outcome (n = 60; 10-y follow-up) shows that low protein levels in the primary breast lesion significantly delineate patients with bad outcome regardless of the tumor HR status (area under the curve = 0.87; 95% CI 0.78-0.96; p = 0.0001). Survival analysis, based on gene expression (n = 375; 25-y follow-up), confirmed that low asporin levels are associated with a reduced likelihood of survival (hazard ratio = 0.58; 95% CI 0.37-0.91; p = 0.017). Although these data highlight the potential of asporin to serve as a prognostic marker, confirmation of the clinical value would require a prospective study on a much larger patient cohort.
Our data show that asporin is a stroma-derived inhibitor of TGF-β1 and a tumor suppressor in breast cancer. High asporin expression is significantly associated with less aggressive tumors, stratifying patients according to the clinical outcome. Future pre-clinical studies should consider options for increasing asporin expression in TNBC as a promising strategy for targeted therapy.
Phosphodiesterase 2 A (PDE2A) is an enzyme involved in the homeostasis of cAMP and cGMP and is the most highly expressed PDE in human brain regions critical for socio-cognitive behavior. In cerebral ...cortex and hippocampus, PDE2A expression level is upregulated in Fmr1-KO mice, a model of the Fragile X Syndrome (FXS), the most common form of inherited intellectual disability (ID) and autism spectrum disorder (ASD). Indeed, PDE2A translation is negatively modulated by FMRP, whose functional absence causes FXS. While the pharmacological inhibition of PDE2A has been associated to its pro-cognitive role in normal animals and in models of ID and ASD, homozygous PDE2A mutations have been identified in patients affected by ID, ASD and epilepsy. To clarify this apparent paradox about the role of PDE2A in brain development, we characterized here Pde2a+/− mice (homozygote animals being not viable) at the behavioral, cellular, molecular and electrophysiological levels. Pde2a+/− females display a milder form of the disorder with reduced cognitive performance in adulthood, conversely males show severe socio-cognitive deficits throughout their life. In males, these phenotypes are associated with microglia activation, elevated glutathione levels and increased externalization of Glutamate receptor (GluR1) in CA1, producing reduced mGluR-dependent Long-term Depression. Overall, our results reveal molecular targets of the PDE2A-dependent pathway underlying socio-cognitive performance. These results clarify the mechanism of action of pro-cognitive drugs based on PDE2A inactivation, which have been shown to be promising therapeutic approaches for Alzheimer's disease, schizophrenia, FXS as well as other forms of ASD.
•Sex-dependent phenotype of Pde2a+/− mice in social discrimination and social interaction•Cognitive deficit in male and female Pde2a+/− mice revealed by the novel object recognition task•-In Pde2a+/ mouse cerebral cortex, an increased number of IBA1+ cells correlates with a reduced number of dendritic spines•mGluR-dependent LTD is reduced in Pde2a+/ CA1 and correlates with an increased phosphorylation level of GluR1
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