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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.
Shao and colleagues present a multiomic analysis of breast tumor samples from Chinese patients, consisting of genomic, transcriptomic, proteomic, metabolomic, radiomic and digital pathology data.
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.
Ganesan and colleagues characterize T cell clonality and transcriptomes at the single-cell level in pediatric brain tumor samples, providing insights into existing tumor neoantigens and T cell responses and the potential for effective immunotherapy.
Bagley et al. conduct a phase 1 trial to study safety and tolerability of CAR T-EGFRvIII cells administered concomitantly with PD-1 inhibition via pembrolizumab in patients with glioblastoma and show tolerability, but without signs of efficacy.
Salvadores and Supek derive three regional mutation density signatures from whole-genome profiles of >4,000 tumors that are associated with cell cycle gene expression and alter somatic mutation rates independently of tissue of origin.
Jin and colleagues show that myeloid cells in patients with colorectal cancer exhibit increased expression of SIRPA and that Sirpa deficiency on macrophages reprograms the tumor microenvironment and enhances the function of antitumor CD8+ T cells.
Yuan and colleagues developed an artificial intelligence-based method to derive growth patterns and morphological features from hematoxylin and eosin-stained slides of lung adenocarcinoma samples, for improved tumor grading and patient prognostication.
Kumar et al. show that the lncRNA Malat1 prevents gasdermin D-mediated pyroptosis induction, in turn suppressing inflammatory cell death and mediating immune evasion and metastasis.
Sherman and colleagues show that ATX suppresses the accumulation of eosinophils in the tumor microenvironment of pancreatic cancer via suppression of CCL11 expression and find that ATX inhibition increases eosinophil influx, promoting tumor cell death.
Leibold and colleagues develop a method to somatically introduce oncogenic lesions into the stomach epithelium, which recapitulates the histological, molecular and clinical features of human gastric cancer.
Warner et al. analyze tumor tissue and ctDNA from patients with de novo metastatic castrate-sensitive prostate cancer and find high intratumoral heterogeneity, suggesting that genomic profiling of multiple samples per patient is needed for accurate outcome prediction.