Selected Articles from This Issue

Pediatric high-grade glioma (PHGG) comprises several aggressive subtypes, with 5-year survival rates ranging from 20% to less than 2%. Despite decades of research, no effective drug therapy has been identified, and radiation therapy remains the only standard of care treatment. PHGG arises from stem-like cells in which epigenetic regulation of transcription through post-translational histone modifications is disrupted. In their study, DeSisto and colleagues identified arginine methyltransferase PRMT5 as potentially important to PHGG tumorigenesis and growth through an shRNA screen of epigenetic regulators. Because PRMT5 expression is essential for survival of non-tumor cells, the authors used shRNA-mediated PRMT5 ablation to evaluate its effects on PHGG growth. Limiting dilution assays showed that PRMT5 abrogation reduced PHGG cells self-renewal. RNA-sequencing and ChIP-sequencing analyses confirmed that PRMT5 alters expression of genes involved in stem cell maintenance and differentiation. In orthotopic xenograft mouse models, PRMT5 depletion increased host survival and reduced tumor aggressiveness. Together, these data suggest that targeting PRMT5 activity in tumorigenic stem-like cells may provide an avenue toward effective PHGG treatment.Survival rates for patients with advanced rhabdomyosarcoma (RMS) have not improved in over 40 years. Because RMS is a pediatric soft tissue sarcoma resembling skeletal muscle precursor cells, differentiation therapy has been proposed. In PAX fusion-negative RMS (FN-RMS), MEK1/2 inhibition promotes differentiation and slows tumor growth; however, the response is short-lived. In this study, Hebron and colleagues identify a novel role for ASAP1, an ARF GTPase-activating protein, along with its preferred substrate, the GTPase ARF1, in myogenic differentiation. They discovered that in FN-RMS, MEK inhibition inactivates WWTR1 (TAZ) in an ASAP1-dependent manner. The loss of ASAP1, ARF1, and additional components of the ARF1 signaling pathway blocks TAZ inactivation, inhibits expression of transcription factors that regulate myogenesis, and impairs differentiation. Furthermore, dual depletion of ASAP1 and WWTR1 restores MEK inhibitor-induced differentiation. This work enhances the understanding of differentiation in FN-RMS and provides justification for investigating RAS pathway and YAP1/TAZ inhibitor combinations in FN-RMS.Colorectal cancer tumors start as polyps on the inner lining of the colorectum, where they are exposed to the mechanics of peristalsis. Leveraging an engineered bioreactor, Clevenger and colleagues externally applied the mechanics of peristalsis to several colorectal cancer cell lines. These experiments revealed a unique malignant mechanoresponse confined to cells with an oncogenic KRAS mutation. Peristalsis enriched cancer stem cell marker LGR5 in KRAS mutant cells, which translated to increased tumorigenicity in vivo. LGR5 enrichment in response to peristalsis was a result of Wnt‐ligand–independent β-catenin activation. Malignant mechanoresponse converged with KRAS pathway dependency via elevated activation of the MEK/ERK effector cascade, validated via both gain and loss of function strategies. This work demonstrated that oncogenic KRAS mutations conferred a unique malignant mechanoresponse to colonic peristalsis in colorectal cancer. In sum, this study lays the foundation to leverage mechanosensory connections to improve the sensitivity of emerging therapies that target oncogenic KRAS.