Issues
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Cover Image
Cover Image
Melanocytes can harbor mutations in oncogenes, including BRAF and NRAS, but not all cells with these mutations display oncogenic competence. In this study, Tagore and colleagues sought to determine if cells within the microenvironment endow oncogenic competence and promote melanoma initiation. Using zebrafish, murine, and human 3D skin reconstruction models, the authors showed that the neurotransmitter GABA is synthesized by melanoma cells and binds to the GABA-A receptor on keratinocytes in the microenvironment, leading to the formation of specialized inhibitory electrochemical cell–cell junctions. GABA blocked the electrical activity between melanoma cells and keratinocytes, and genetic and pharmacologic modulation of GABA signaling enhanced the initiation and growth of melanoma in vivo. Together, these results suggest that communication between melanoma cells and keratinocytes within the microenvironment promotes tumor initiation and that GABAergic signaling may serve as a potential therapeutic target in this disease. For more information, see the article by Tagore and colleagues on page 2270. Artwork by Bianca Dunn. - PDF Icon PDF LinkTable of Contents
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In This Issue
In the Spotlight
Reviews
Research Briefs
The Origin of Highly Elevated Cell-Free DNA in Healthy Individuals and Patients with Pancreatic, Colorectal, Lung, or Ovarian Cancer
Cell-free DNA (cfDNA) methylation patterns were used to determine that leukocytes, rather than neoplastic cells or surrounding normal epithelial cells, generally contributed to the excess cfDNA found in patients with cancer.
Early-Stage Breast Cancer Detection in Breast Milk
The presence of cell-free tumor DNA was reported in breast milk from patients with breast cancer, and its use as a screening method surpassed plasma liquid biopsy in terms of detecting and molecularly profiling early-stage tumors, even prior to diagnosis.
Research Articles
Colorectal Cancer Organoid–Stroma Biobank Allows Subtype-Specific Assessment of Individualized Therapy Responses
A biobank of colorectal cancer organoids with matched cancer-associated fibroblasts was generated and serves as a preclinical model that can determine the impact of the tumor microenvironment on transcriptomic subtypes and sensitivity to therapeutic drugs.
Dual Immune Checkpoint Blockade Induces Analogous Alterations in the Dysfunctional CD8+ T-cell and Activated Treg Compartment
Patients with head and neck squamous cell carcinoma that responded to dual PD-1/CTLA4 immune checkpoint blockade exhibited a parallel remodeling of the activated CD4+ regulatory T-cell (Treg) and dysfunctional CD8+ T-cell compartments.
Inhibition of METTL3 Results in a Cell-Intrinsic Interferon Response That Enhances Antitumor Immunity
Inhibiting the catalytic activity of METTL3 revealed potent antitumor activity both as a single agent and in combination with anti–PD-1 therapy, providing preclinical rationale for targeting RNA methylation as a potential immunotherapeutic approach.
An Inflammatory Checkpoint Generated by IL1RN Splicing Offers Therapeutic Opportunity for KRAS-Mutant Intrahepatic Cholangiocarcinoma
An inflammatory checkpoint generated by mRNA splicing of IL1RN can inhibit a mutant KRAS–mediated inflammatory cascade, tumor progression, and resistance to immunotherapy in cholangiocarcinoma, providing a potential therapeutic option for KRAS-mutant cancers.
GABA Regulates Electrical Activity and Tumor Initiation in Melanoma
The neurotransmitter GABA was identified as a mediator of functional communication within the melanoma microenvironment, which highlights the role of electrical activity in melanoma initiation and suggests GABA as a potential therapeutic target in this disease.
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