Highlights of This Issue

Abstract

Despite therapeutic advances, glioblastoma burden inevitably progresses or relapses. There is accumulating evidence that glutathione and system xc–, a cystine transporter, mediates resistance of various cancers to cytotoxin-based therapies. In the current study, Polewski and colleagues discover that overexpression of SLC7A11, the catalytic subunit of system xc–, increases chemoresistance of glioma cells to temozolimide (TMZ) and alters cancer metabolism. This is the first report that links SLC7A11 overexpression with increased oxidative phosphorylation and ATP production to fulfill energy requirements while maintaining low ROS levels. Therefore, targeting SLC7A11 may be a promising therapeutic strategy for glioblastoma patients.Fibronectin and its fragments derived from bone-marrow mesenchymal stromal cells induce migratory and adhesive responses via the α5β1 integrin in PTEN-null prostate cancer cells, representing a seed-and-soil principle relevant to bone metastases, the lethal phenotype of prostate cancer. Here, α5 integrin knockdown downregulates the BCL-2 family of pro-apoptotic molecules and induces apoptosis. Chemical parsing indicates that potent BCL-XL inhibition specifically synergizes with PI3K/AKT inhibitors to induce synthetic lethality in PTEN-null prostate cancer cells. Given the importance of PTEN-loss in the progression of disease in prostate cancer, these findings are of significant translational relevance.Colon cancers classify into various molecular subtypes with diverse characteristics. In this study, McNew and colleagues determine sensitivity profiles to MEK and TAK1 kinase inhibition in a panel of colon cancer cell lines. MEK and TAK1 inhibition had strong apoptotic effects in cells displaying KRAS-dependent activation of pro-inflammatory signaling. Pro-inflammatory signaling in the context of KRAS/MEK and TAK1 dependency promotes tumor cell survival. Furthermore, a Wnt/NFkB transcriptional signature was derived that associates with KRAS dependency. Combined activation of Wnt/NFkB signaling associates with poor patient prognosis and could reveal subsets of colon cancers that are MEK- and TAK1-dependent.The ability of cells to sense and process information from the extracellular matrix (ECM) is of critical importance to understanding malignancy. Moreover, proteoglycans and their multitude of glycosaminoglycan (GAG) modifications are fundamental to the cells capacity to integrate this information. Clausen and colleagues, using a recombinant protein (rVAR2) derived from Plasmodium falciparum, demonstrate that the oncofetal chondroitin sulfate (ofCS) GAG regulates cancer cell motility through integrins and that blocking ofCS inhibits integrin signaling and metastatic phenotypes. Importantly, evidence is also provided that both human and murine metastatic lesions express high levels of ofCS; thus, suggesting ofCS as a universal cancer-specific marker and therapeutic target.