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.

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.

Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid β-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBPα methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-γ coactivator-1 PGC1α upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors.

Proteoglycans play a key role in cancer development and progression by participating in the constitution of a specific fertile tumor microenvironment. As they are largely overexpressed in the malignant stroma, proteoglycans provide a reservoir of potential new targets for anticancer therapies, because they can serve to convey toxic payloads in the close proximity of cancer cells and subsequently destroy them. In this context, versican, a proteoglycan largely overexpressed in several solid cancers, bears the potential to be such an ideal target. As 4 main versican isoforms have been characterized, we sought to determine which isoform could represent the best target in human breast cancer. We used a series of 10 primary breast cancer lesions that were characterized as overexpressing the versican protein, when compared with matched normal breast tissues, using shotgun mass spectrometry and immunohistochemistry experiments. Quantitative polymerase chain reaction and western‐blotting experiments were used to evaluate versican isoform expression in breast cancer/normal tissue pairs for which ARN quality was excellent. All known isoforms were significantly overexpressed in the malignant lesions, both at the mRNA and at the protein levels. In the course of this study, we also identified and cloned a new alternatively spliced versican isoform, referred to as V4, which was also found to be upregulated in human breast cancer. This study provides for the first time a comprehensive mRNA and protein analysis of versican isoforms expression in human breast tissues, and offers insights into which therapeutic strategy would be best suited to target versican in human breast cancer lesions.

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.

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. Breast cancer is the most common cancer in women worldwide. Nearly 1.7 million new cases were diagnosed in 2012, and half a million women died from the disease. Breast cancer begins when cells in the breast that normally make milk (epithelial cells) acquire genetic changes that allow them to divide uncontrollably and to move around the body (metastasize). Uncontrolled cell division leads to the formation of a lump that can be detected by mammography (a breast X-ray) or by manual breast examination. Breast cancer is treated by surgical removal of the lump or, if the cancer has started to spread, by removal of the whole breast (mastectomy). After surgery, women often receive chemotherapy or radiotherapy to kill any remaining cancer cells, and women whose tumors express receptors for the female sex hormones estrogen and progesterone or for HER2, a growth factor receptor, are treated with drugs that block these receptors; estrogen, progesterone, and HER2 all control breast cell growth. Nowadays, the prognosis (outlook) for women living in high-income countries who develop breast cancer is generally good—nearly 90% of such women are still alive five years after diagnosis. The cells surrounding cancer cells—cancer-associated fibroblasts and other components of the stroma—support cancer growth and metastasis and are good targets for new cancer therapies. But, although there is mounting evidence that cancer cells actively adapt the stroma so that it produces various factors the tumor needs to grow and spread, very few molecules produced by the stroma that might serve as targets for drug development have been identified. Here, the researchers investigate whether a molecule called asporin might represent one such target. Asporin, which is highly expressed in the stroma of breast tumors, inhibits a growth factor called TGF-β1. TGF-β1 is involved in maintaining healthy joints, but is also a key molecule in the development of metastatic breast cancer. Most particularly, it modulates an important step in metastasis called the epithelial to mesenchymal transition and it regulates “stemness” in cancer cells. Stem cells are a special type of cell that can multiply indefinitely; tumor cells often look and behave very much like stem cells. Using a technique called immunohistochemistry, the researchers first showed that asporin is highly expressed in the stroma of most human breast cancers but not in normal breast tissue. Next, they showed that breast fibroblasts secrete asporin when exposed to conditioned medium from some human breast cancer cell lines (breast cancer cells adapted to grow continuously in the laboratory; conditioned medium is the solution in which cells have been grown). Specifically, conditioned medium from hormone receptor positive cells induced strong asporin expression by breast fibroblasts, whereas medium from breast cancer cells not expressing estrogen or progesterone receptors or HER2 receptors (triple-negative breast cancer cells) suppressed asporin expression. Other experiments showed that TGF-β1 secreted by breast cancer cells induces asporin expression in breast fibroblasts, and that asporin, in turn, inhibits TGF-β1-mediated induction of the epithelial to mesenchymal transition and stemness in breast cancer cells. Triple negative breast cancers appear to inhibit stromal expression of asporin at least in part via expression of the soluble signaling protein interleukin-1β. Notably, in mouse models of triple-negative breast cancer, tumors engineered to express asporin grew slower and metastasized less than tumors not expressing asporin. Finally, among women with breast cancer, asporin expression was low in triple-negative and HER2-positive tumors but significantly higher in hormone receptor positive tumors, and low asporin levels in primary breast lesions were associated with a reduced likelihood of survival independent of hormone receptor and HER2 expression. These findings suggest that asporin is a stroma-derived inhibitor of TGF-β1 and a tumor suppressor in breast cancer. Importantly, they also provide preliminary evidence that high asporin expression is associated with less aggressive tumors (hormone receptor positive tumors), whereas low asporin expression is associated with more aggressive tumors (triple negative tumors and HER2-positive tumors). Thus, asporin expression might provide a new prognostic marker for breast cancer. However, before asporin can be used as a biomarker to predict outcomes in women with breast cancer and to identify those women in need of more aggressive treatment, these findings need to be confirmed in large prospective clinical studies. If these findings are confirmed, methods for increasing asporin expression in the stromal tissues of triple negative breast cancer could be a promising strategy for targeted therapy for this group of breast cancers, which currently have a poor prognosis. This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001871.