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Rich and colleagues show that glioblastoma stem cells have increased global protein translation, which is achieved via the tRNA modifier YRDC. They show that targeting it or reducing its substrate threonine suppresses tumor growth.
Dobrin et al. develop a fusion receptor comprising the CD80 ectodomain and the 4-1BB cytoplasmic domain, which engages the CD28 and 4-1BB pathways and increases the antitumor potency of HLA-independent (HIT) and TCR-engineered T cells.
Ubhi et al. describe the contribution of APOBEC family members A3C and A3D in the gemcitabine resistance mechanism in the context of pancreatic cancer, which is mediated by facilitating the restart of treatment-induced stalled replication forks.
Ideker and colleagues present NeST-VVN, a deep learning model based on cancer protein assembly data that can be used to predict the response and resistance of cancer cells to CDK4/6 inhibitors.
Subramanian et al. use the EcoTyper machine-learning framework to characterize the tumor, immune and stromal cell states and ecosystems that comprise sarcomas.
Through in vivo tracking of tumor-specific CD8+ T cells in response to immunotherapy in mice, Barboy et al. characterize the tumor response to anti-PD-1 therapy and optimize a combination treatment with anti-4-1BB agonist.
De Blank and colleagues examine data from childhood cancer survivors diagnosed between 1970 and 1999 and find that exposure to radiation decreased over time, and radiation was associated with a higher risk of late mortality and subsequent neoplasms.
Dong et al. demonstrate that targeting arginine N-methyltransferase 9 (PRMT9) inhibits cancer stem cells in the context of acute myeloid leukemia via type I interferon-associated immunity. Furthermore, they show that PRMT9 inhibition synergizes with anti-programmed cell death protein 1.
Roussos-Torres and colleagues perform a phase Ib clinical trial of entinostat, nivolumab and ipilimumab in individuals with advanced HER2-negative breast cancer, report on safety and response and characterize the immune-modulatory effects.
Schmid and colleagues show that pancreatic cancer cell colonization of the liver is accompanied by low-grade tissue injury and efferocytosis, which promotes reprogramming of macrophages and upregulation of arginase.
Benoit and colleagues identify the dopamine transporter antagonist vanoxerine as a suppressor of G9a methyltransferase and show that treatment leads to cancer stem cell suppression and restoration of an immunoresponsive tumor microenvironment in CRC.
Roland et al. report the results of a randomized, non-comparative phase 2 trial of neoadjuvant nivolumab or a combination of nivolumab and ipilimumab in patients with resectable retroperitoneal dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma.
Jakab et al. show that metastasizing tumor cells have a predetermined methylation status that allows them to respond differentially to endothelial cell niche-derived Wnt signals, resulting in either latency or intravascular proliferation.
Zheng et al. generate and utilize a biobank of colorectal cancer PDOs to find that high LGR4 is linked to chemoresistance. They develop a monoclonal antibody against LGR4 that activates ferroptosis and is therapeutically beneficial.
Gammage and colleagues find that mitochondrial DNA mutations induce alterations in redox metabolism, a remodeled tumor microenvironment characterized by a loss of neutrophils and consequently enhanced responses to immunotherapy in melanoma.
Izar and colleagues demonstrate that loss of Pip4k2c in melanoma cells promotes liver metastatic tropism driven by PI3K-AKT pathway activation in the insulin-rich liver milieu, which can be abrogated by inhibition of SGLT2 or a ketogenic diet.
Chaib et al. find that therapy-induced senescent cells have high programmed cell death 1 ligand 2 (PD-L2), contributing to recurrence. They show that PD-L2 blocking combined with chemotherapy is therapeutically beneficial because it reduces senescent cells and immunosuppressive cell recruitment.
Huang et al. show that ADAM9 loss upregulates PAI-1, promoting its interaction with KRAS and resulting in selective lysosomal degradation of KRAS. They also identify a small-molecule inhibitor of ADAM9 with therapeutic benefits in the context of PDAC.
Theodorescu and colleagues describe a Molecular Twin approach that integrates multi-omic and computational pathology data from patients with pancreatic ductal adenocarcinoma using artificial intelligence to predict clinical outcomes.
Manchado and colleagues combine CRISPR screening and transcriptomics to identify INPP5A as a dependency and therapeutic target in uveal melanoma driven by mutations in GNAQ/GNA11 and show that IP4 levels correlate with sensitivity to INPP5A loss.