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Metastasis is a major contributor to breast cancer mortality, but the mechanisms that underlie the different stages of the metastatic process in this disease are not yet fully understood. Yofe, Shami, Cohen, Landsberger, and colleagues sought to investigate the cellular and molecular events that shape metastatic niches by applying the spatial NICHE-seq technology to a spontaneous model of breast cancer lung metastasis. A map of the immune microenvironment in single-cell resolution during distinct stages and spanning different metastatic regions was created and revealed profound differences between the primary and lung metastatic tumor microenvironments. Premetastatic lungs demonstrated infiltration of both inflammatory neutrophils and monocytes while an accumulation of suppressive monocytes and macrophages, as well as conventional type 2 dendritic cells and regulatory T cells, was observed at the onset of metastases. Moreover, spatial analyses indicated that metastasis-associated immune cells were located at the metastatic core with the exception of TREM2+ regulatory macrophages, which were observed at the metastatic invasive margin in both humans and mice. These TREM2+ regulatory macrophages support an immunosuppressive niche at the invasive margin, suggesting their role as modulators of the metastatic microenvironment. Together, these results reveal key alterations to the immune molecular state during the metastatic cascade and point to myeloid checkpoints to improve cancer immunotherapy strategies. For more information, see the article by Yofe, Shami, Cohen, Landsberger, and colleagues on page 2610. - PDF Icon PDF LinkTable of Contents
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Highlights of FDA Oncology Approvals in 2023: Bispecific T-cell Engagers, Pediatric Indications, and Inclusive Drug Development
Research Articles
Ultrasensitive Detection of Circulating LINE-1 ORF1p as a Specific Multicancer Biomarker
Expression of the transposon protein LINE-1 ORF1p is pervasive in cancer, and the development of improved plasma ORF1p assays demonstrated highly specific pan-cancer utility with promise in early detection, monitoring, and prognostics.
Structural Basis of PML-RARA Oncoprotein Targeting by Arsenic Unravels a Cysteine Rheostat Controlling PML Body Assembly and Function
A PML B-box-2 crystal structure was revealed that drives B2 trimer assembly and the positioning of a cysteine trio to create an ideal arsenic-binding pocket, with both B2 trimerization and the cysteine trio being mandatory for PML-mediated functions, including an oxidative stress response.
Formate Supplementation Enhances Antitumor CD8+ T-cell Fitness and Efficacy of PD-1 Blockade
Metabolic support, in the form of formate supplementation, combined with anti–PD-1 improves antitumor CD8+ T-cell fitness and tumor control, revealing a strategy that can be used to extend the benefits of anti–PD-1 therapy.
Master Transcription Factor Reprogramming Unleashes Selective Translation Promoting Castration Resistance and Immune Evasion in Lethal Prostate Cancer
The master transcription factor MITF transcriptionally regulates eIF3B expression which, in turn, reprograms the translatome of specific mRNAs, including androgen receptor and MHC-I, leading to a targetable mRNA translation dependence that delays prostate cancer progression.
Spatial and Temporal Mapping of Breast Cancer Lung Metastases Identify TREM2 Macrophages as Regulators of the Metastatic Boundary
Temporal and spatial mapping of the immune landscape of breast cancer lung metastases identified a distinct TREM2+ macrophage population located at metastatic margins, that suppress antitumor responses, indicating a potential target for cancer immunotherapies.
p53 Gain-of-Function Mutation Induces Metastasis via BRD4-Dependent CSF-1 Expression
A common TP53 gain-of-function mutation, R172H, forms a complex with BRD4, leading to increased expression of CSF-1 and ensuing tumor metastasis of esophageal squamous cell carcinoma, thereby opening a pathway for new therapeutic avenues.
Oncogenic KRAS Drives Lipofibrogenesis to Promote Angiogenesis and Colon Cancer Progression
Fibroblast transformation impacts the progression of oncogenic KRAS-driven colorectal cancer (CRC), resulting in VEGFA production that fuels angiogenesis, which unveils a potential therapeutic option for patients with mutant KRAS-driven CRC.
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