Cancer research最新文献

Tissue-specific differences in the expression of paralog genes, which are not essential in most cell types due to the buffering effect of the partner pair, can make for highly selective gene dependencies. To identify selective paralogous targets for acute myeloid leukemia (AML), we integrated the Cancer Dependency Map with numerous datasets characterizing protein-protein interactions, paralog relationships, and gene expression in cancer models. In this study, we identified ATP1B3 as a context-specific, paralog-related dependency in AML. ATP1B3, the β-subunit of the sodium-potassium pump (Na/K-ATP pump), interacts with the α-subunit ATP1A1 to form an essential complex for maintaining cellular homeostasis and membrane potential in all eukaryotic cells. When ATP1B3's paralog ATP1B1 is poorly expressed, elimination of ATP1B3 leads to the destabilization of the Na/K-ATP pump. ATP1B1 expression is regulated through epigenetic silencing in hematopoietic lineage cells through histone and DNA methylation in the promoter region. Loss of ATP1B3 in AML cells induced cell death in vitro and reduced leukemia burden in vivo, which could be rescued by stabilizing ATP1A1 through overexpression of ATP1B1. Thus, ATP1B3 is a potential therapeutic target for AML and other hematologic malignancies with low expression of ATP1B1. Significance: ATP1B3 is a lethal selective paralog dependency in acute myeloid leukemia that can be eliminated to destabilize the sodium-potassium pump, inducing cell death.

Patients with breast cancer with estrogen receptor-positive tumors face a constant risk of disease recurrence for the remainder of their lives. Dormant tumor cells residing in tissues such as the bone marrow may generate clinically significant metastases many years after initial diagnosis. Previous studies suggest that dormant cancer cells display "stem-like" properties (cancer stem cell, CSC), which may be regulated by the immune system. To elucidate the role of the immune system in controlling dormancy and its escape, we studied dormancy in immunocompetent, syngeneic mouse breast cancer models. Three mouse breast cancer cell lines, PyMT, Met1, and D2.0R, contained CSCs that displayed short- and long-term metastatic dormancy in vivo, which was dependent on the host immune system. Each model was regulated by different components of the immune system. Natural killer (NK) cells were key for the metastatic dormancy phenotype in D2.0R cells. Quiescent D2.0R CSCs were resistant to NK cell cytotoxicity, whereas proliferative CSCs were sensitive. Resistance to NK cell cytotoxicity was mediated, in part, by the expression of BACH1 and SOX2 transcription factors. Expression of STING and STING targets was decreased in quiescent CSCs, and the STING agonist MSA-2 enhanced NK cell killing. Collectively, these findings demonstrate the role of immune regulation of breast tumor dormancy and highlight the importance of utilizing immunocompetent models to study this phenomenon. Significance: The immune system controls disseminated breast cancer cells during disease latency, highlighting the need to utilize immunocompetent models to identify strategies for targeting dormant cancer cells and reducing metastatic recurrence. See related commentary by Cackowski and Korkaya, p. 3319.

Changes in the composition and physical properties of the tumor extracellular matrix are linked to poor cytotoxic T-cell infiltration and therapy response, yet the underlying mechanisms remain unclear. Tharp and colleagues revealed a fascinating cascade where tumor fibrosis alters macrophage metabolism, restricting the nutrients available to infiltrating T cells and resulting in their suppression and exclusion from the tumor microenvironment. This study suggests that targeting metabolic pathways could be a promising strategy to overcome the immune suppression induced by the tumor extracellular matrix.