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1.
Sci Adv ; 8(45): eabm3548, 2022 11 11.
Article in English | MEDLINE | ID: mdl-36351009

ABSTRACT

Metastasis is responsible for most breast cancer-related deaths; however, identifying the cellular determinants of metastasis has remained challenging. Here, we identified a minority population of immature THY1+/VEGFA+ tumor epithelial cells in human breast tumor biopsies that display angiogenic features and are marked by the expression of the oncogene, LMO2. Higher abundance of LMO2+ basal cells correlated with tumor endothelial content and predicted poor distant recurrence-free survival in patients. Using MMTV-PyMT/Lmo2CreERT2 mice, we demonstrated that Lmo2 lineage-traced cells integrate into the vasculature and have a higher propensity to metastasize. LMO2 knockdown in human breast tumors reduced lung metastasis by impairing intravasation, leading to a reduced frequency of circulating tumor cells. Mechanistically, we find that LMO2 binds to STAT3 and is required for STAT3 activation by tumor necrosis factor-α and interleukin-6. Collectively, our study identifies a population of metastasis-initiating cells with angiogenic features and establishes the LMO2-STAT3 signaling axis as a therapeutic target in breast cancer metastasis.


Subject(s)
Breast Neoplasms , Lung Neoplasms , Humans , Mice , Animals , Female , Breast Neoplasms/pathology , Lung Neoplasms/metabolism , Signal Transduction , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , LIM Domain Proteins/genetics , LIM Domain Proteins/metabolism
2.
Nature ; 501(7467): 380-4, 2013 Sep 19.
Article in English | MEDLINE | ID: mdl-24025767

ABSTRACT

Down's syndrome results from full or partial trisomy of chromosome 21. However, the consequences of the underlying gene-dosage imbalance on adult tissues remain poorly understood. Here we show that in Ts65Dn mice, which are trisomic for 132 genes homologous to genes on human chromosome 21, triplication of Usp16 reduces the self-renewal of haematopoietic stem cells and the expansion of mammary epithelial cells, neural progenitors and fibroblasts. In addition, Usp16 is associated with decreased ubiquitination of Cdkn2a and accelerated senescence in Ts65Dn fibroblasts. Usp16 can remove ubiquitin from histone H2A on lysine 119, a critical mark for the maintenance of multiple somatic tissues. Downregulation of Usp16, either by mutation of a single normal Usp16 allele or by short interfering RNAs, largely rescues all of these defects. Furthermore, in human tissues overexpression of USP16 reduces the expansion of normal fibroblasts and postnatal neural progenitors, whereas downregulation of USP16 partially rescues the proliferation defects of Down's syndrome fibroblasts. Taken together, these results suggest that USP16 has an important role in antagonizing the self-renewal and/or senescence pathways in Down's syndrome and could serve as an attractive target to ameliorate some of the associated pathologies.


Subject(s)
Down Syndrome/metabolism , Down Syndrome/pathology , Neural Stem Cells/metabolism , Neural Stem Cells/pathology , Ubiquitin Thiolesterase/metabolism , Adult Stem Cells/metabolism , Adult Stem Cells/pathology , Animals , Cell Proliferation , Cellular Senescence , Chromosomes, Human, Pair 21/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Disease Models, Animal , Down Syndrome/genetics , Epithelium/metabolism , Female , Fibroblasts/cytology , Fibroblasts/metabolism , Fibroblasts/pathology , Gene Dosage , Gene Expression Regulation , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/pathology , Humans , Mammary Glands, Animal/cytology , Mammary Glands, Animal/metabolism , Mice , Molecular Targeted Therapy , Trisomy/genetics , Ubiquitin Thiolesterase/genetics , Ubiquitination
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