BST-2 promotes survival in circulation and pulmonary metastatic seeding of breast cancer cells

Abstract

Bone marrow stromal antigen 2 (BST-2) mediates various facets of cancer progression and metastasis. Here, we show that BST-2 is linked to poor survival in invasive breast cancer patients as its expression positively correlates with disease severity. However, the mechanisms that drive the pro‐metastatic functions of BST-2 are not fully understood. Correlation of BST-2 expression and tumor aggressiveness was analyzed in human tissue samples. Migration, invasion, and competitive experimental metastasis assays were used to measure the cellular responses after silencing BST-2 expression. Using a mouse model of breast cancer, we show that BST-2 promotes metastasis independent of the primary tumor. Additional experiments show that suppression of BST-2 renders non-adherent cancer cells non-viable by sensitizing cells to anoikis. Embedment of cancer cells in basement membrane matrix reveals that silencing BTS-2 expression inhibits invadopodia formation, extracellular matrix degradation, and subsequent cell invasion. Competitive experimental pulmonary metastasis shows that silencing BST-2 reduces the numbers of viable circulating tumor cells (CTCs) and decreases the efficiency of lung colonization. Our data define a previously unknown function for BST-2 in the i) formation of invadopodia, ii) degradation of extracellular matrix, and iii) protection of CTCs from hemodynamic stress. We believe that physical (tractional forces) and biochemical (ECM type/composition) cues may control BST-2’s role in cell survival and invadopodia formation. Collectively, our findings highlight BST-2 as a key factor that allows cancer cells to invade, survive in circulation, and at the metastatic site.

Development and Characterization of the Shortest Anti-Adhesion Peptide Analogue of B49Mod1

“…In addition, it has been suggested that increased immune cell adhesion and resistance of cancer cells to tamoxifen-induced apoptosis is linked to BST-2 expression [27,28,30]. We have also shown that the silencing of BST-2 in murine and human breast cancer cell lines results in a shift from a highly aggressive to a non-aggressive phenotype, including loss of cell to cell and cell to ECM adhesion [24,29], decrease in anchorage-independent growth/survival, formation of invadopodia for ECM remodeling, migration, and invasion [31]. Together, these findings suggest a potential for BST-2 as a valuable therapeutic target.…”

The Role of Circulating Tumor Cells in the Metastatic Cascade: Biology, Technical Challenges, and Clinical Relevance

“…TAMs promote tumor cell invasion and consequently tumor progression [31]. They also secrete interferon molecules (IFN) that induce overexpression of bone marrow stromal antigen 2 (BST-2), a type II transmembrane protein that supports metastasis formation by mediating CTC survival, invasion, and dissemination [33]. Overall, CTC dynamic state between epithelial or mesenchymal states [1,29] and the heterotypic interactions among the different cell types within a cluster are critical for their survival and collective invasion [34].…”

“…CTC clusters could be targeted with agents that exploit the presence of TAMs [31] and neutrophils [75] in such clusters (e.g., immune checkpoint blockade antibodies and targeting therapy). Moreover, TAM-derived IFNs induce BST-2 overexpression that supports metastasis formation [33]. In a mouse model of breast cancer, BST-2 silencing reduces CTC number and lung metastases [33].…”

“…Moreover, TAM-derived IFNs induce BST-2 overexpression that supports metastasis formation [33]. In a mouse model of breast cancer, BST-2 silencing reduces CTC number and lung metastases [33]. Therefore, BST-2 might represent a candidate therapeutic target for metastatic disease.…”

Uncovering Transcriptional Dark Matter via Gene Annotation Independent Single-Cell RNA Sequencing Analysis

“…3C). H3F3C is a novel unannotated gene that plays a role in maintaining nucleosome structure 33,34 while BST2 is associated with interferon gamma and other cytokine signaling pathways in the immune system 35,36 . Differentially expressed naked mole rat uTARs were also identified within neutrophils, T cells, and macrophages ( Fig.…”