Selected Articles from This Issue

Abstract

Glioblastoma multiforme (GBM) is a highly aggressive cancer characterized by drug resistance and invasion. While it has been recognized that gap junctions (GJ) between GBM tumor cells and adjacent astrocytes are important for GBM invasion, the molecular mechanisms by which GJ contribute to GBM cell invasion have yet to be described. In their study, McCutcheon and Spray query the role of GJ protein Connexin 43 (Cx43) in GBM cell invasion via Cx43 genetic ablation and pharmacological inhibition in GBM cell line-astrocyte co-cultures and ex vivo brain organotypic slice cultures. The authors reveal a dichotomous function of Cx43 in GBM cell invasion, where Cx43 inhibition in GBM cells enhances GBM cell invasion and Cx43 inhibition in astrocytes abrogates GBM cell invasion. Transcriptomics analysis implicated miR-19b in the mechanism underlying the role of Cx43 in GBM cell invasion, an implication that was confirmed both in vitro and ex vivo. Overall, the study unveils a previously unknown mechanism governing GBM cell invasion that could inform targeted GBM therapeutic strategies moving forward.While dysregulated Notch signaling has been implicated in multiple cancer types, the role(s) of MIB1, an E3 ubiquitin ligase that is key for Notch signaling, in cancer has yet to be defined. Wang and colleagues show that MIB1 expression is increased in some lung squamous carcinomas and lung adenocarcinomas relative to adjacent healthy tissues, and that elevated MIB1 expression correlates with poor patient survival. Using a stably transduced MIB1 overexpressing cell line, the authors demonstrate that MIB1 can induce epithelial–mesenchymal transition and tumor cell motility. Conversely, eliminating MIB1 via CRISPR/Cas9 induced a more epithelial phenotyp. characterized by reduced tumor cell motility. The authors also find that MIB1 renders lung cancer cells susceptible to death induced by glutathione peroxidase 4 inhibitor RSL3, suggesting MIB1 expression sensitizes tumor cells to ferroptosis. Correspondingly, the authors show that MIB1 ubiquitinates master antioxidant transcription factor NRF2, allowing lipid peroxide accumulation and subsequent ferroptosis. Altogether, the data presented elucidate how MIB1 can contribute to tumorigenesis and suggest that patients bearing tumors with elevated MIB1 expression may benefit from treatment with ferroptosis-inducing agents.FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations are prevalent in acute myeloid leukemia (AML) and are associated with poor prognoses. Existing FLT3 inhibitors can induce drug resistance and lose efficacy against AML, making combinatorial therapeutic approaches against FLT3-ITD–mutant AML an area of interest. By querying transcriptomes of FLT3-ITD–mutant AML cell lines treated with FLT3 inhibitors, Zhang and colleagues observed that FLT3-ITD mutations correlate with increased expression of de novo creatine biosynthesis pathway components. Accordingly, the authors found that FLT3-ITD–mutant AML cells contain heightened levels of creatine and ATP. The authors discovered that FLT3-ITD mutations increase de novo creatine biosynthesis in part via STAT5-mediated transcription of glycine amidinotransferase (AGAT), a critical enzyme in the creatine biosynthetic pathway. A creatine analog and shRNA-mediated AGAT ablation increased FLT3-ITD–mutant AML cell apoptosis and decreased proliferation, and each approach synergized with FLT3 inhibition to impede AML cell proliferation and survival in vitro. Overall, the study elucidates a previously unknown mechanism by which FLT3-ITD mutations promote AML and provides a new therapeutic target for patients with AML harboring FLT3-ITD mutations.Human papillomaviruses (HPV) are causally linked to several cancers, but molecular host–pathogen interactions underlying oncogenesis have not been fully elucidated. In their study, Mirza and colleagues show that Ecdysoneless (ECD), the human homolog of the Drosophila ecdysoneless gene, is highly expressed in head and neck squamous cell carcinoma cell lines as well as cervical cancer cell lines and tumor samples. Using in vitro protein–protein binding and cellular immunoprecipitation assays, the authors demonstrate that ECD binds to high-risk HPV E6 oncoprotein. Ablating ECD expression using siRNA revealed that ECD participates in E6 RNA splicing, as well as splicing of cellular mRNA encoding proteins that are critical for HPV-driven oncogenesis. Disruption of ECD expression also abrogated cervical cancer cell line colony formation, migration, and invasion, further supporting the finding that ECD contributes to HPV-driven oncogenesis. Taken together, the presented data further clarify molecular HPV-host interactions underlying HPV-driven oncogenesis and provide a potential novel therapeutic target for HPV-positive cancers.