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1.
Cell Metab ; 35(10): 1688-1703.e10, 2023 10 03.
Article in English | MEDLINE | ID: mdl-37793345

ABSTRACT

Metastasis causes breast cancer-related mortality. Tumor-infiltrating neutrophils (TINs) inflict immunosuppression and promote metastasis. Therapeutic debilitation of TINs may enhance immunotherapy, yet it remains a challenge to identify therapeutic targets highly expressed and functionally essential in TINs but under-expressed in extra-tumoral neutrophils. Here, using single-cell RNA sequencing to compare TINs and circulating neutrophils in murine mammary tumor models, we identified aconitate decarboxylase 1 (Acod1) as the most upregulated metabolic enzyme in mouse TINs and validated high Acod1 expression in human TINs. Activated through the GM-CSF-JAK/STAT5-C/EBPß pathway, Acod1 produces itaconate, which mediates Nrf2-dependent defense against ferroptosis and upholds the persistence of TINs. Acod1 ablation abates TIN infiltration, constrains metastasis (but not primary tumors), bolsters antitumor T cell immunity, and boosts the efficacy of immune checkpoint blockade. Our findings reveal how TINs escape from ferroptosis through the Acod1-dependent immunometabolism switch and establish Acod1 as a target to offset immunosuppression and improve immunotherapy against metastasis.


Subject(s)
Breast Neoplasms , Carboxy-Lyases , Ferroptosis , Humans , Mice , Animals , Female , Breast Neoplasms/metabolism , Neutrophils , Carboxy-Lyases/metabolism , Melanoma, Cutaneous Malignant
2.
Biochim Biophys Acta Mol Basis Dis ; 1867(7): 166151, 2021 07 01.
Article in English | MEDLINE | ID: mdl-33892077

ABSTRACT

Despite recent development of next-generation androgen receptor (AR) antagonists, metastatic castration-resistant prostate cancer (CRPC) remains incurable and requires deeper understanding through studies in suitable animal models. Prostate-specific deletion of Pten and Smad4 in mice recapitulated the disease progression of human prostate adenocarcinoma, including metastasis to lymph nodes and lung. Moreover, Pten/Smad4 tumors fostered an immunosuppressive microenvironment dominated by myeloid-derived suppressor cells (MDSCs). However, the response of Pten/Smad4 tumors to androgen deprivation and anti-androgen therapies has not been described. Here, we report that the combination of surgical castration and enzalutamide treatment in Pten/Smad4 mice slowed down the tumor growth and prolonged the median survival of the mice for 8 weeks. Treatment-naïve and castration-resistant primary tumors exhibited comparable levels of immune infiltrations with the exception of reduced monocytic MDSCs in CRPC. RNA profiling of treatment-naïve and castration-resistant primary tumors revealed largely preserved transcriptome with modest expressional alterations of collagen-related and immune-related genes, among which CC chemokine receptor type 2 (Ccr2) downregulation and predicted negative activation in CRPC was consistent with reduced monocytic MDSC infiltration. Importantly, significant transcriptomic reprograming was observed in lung metastatic CRPC compared with primary CRPC and enriched for immune-related and coagulation-related pathways. At the individual gene level, we validated the expression changes of some of the most upregulated (Cd36, Bmp5, Bmp6, Etv5, Prex2, Ptprb, Egfl6, Itga8 and Cxcl12) and downregulated genes (Cxcl9 and Adamts5). Together, this study uncovers the inherent activity of Pten/Smad4 tumors to progress to CRPC and highlights potentially targetable transcriptomic signatures associated with CRPC metastasis.


Subject(s)
Androgen Antagonists/pharmacology , Disease Models, Animal , Gene Expression Regulation, Neoplastic/drug effects , Lung Neoplasms/drug therapy , Prostatic Neoplasms, Castration-Resistant/drug therapy , Transcriptome/drug effects , Animals , Apoptosis , Cell Proliferation , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/secondary , Male , Mice , Mice, Knockout , PTEN Phosphohydrolase/physiology , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/metabolism , Prostatic Neoplasms, Castration-Resistant/pathology , Smad4 Protein/physiology , Tumor Cells, Cultured
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