4 research outputs found
Soluble ephrin a1 is necessary for the growth of HeLa and SK-BR3 cells
<p>Abstract</p> <p>Background</p> <p>Ephrin A1 (EFNA1) is a member of the A-type ephrin family of cell surface proteins that function as ligands for the A-type Eph receptor tyrosine kinase family. In malignancy, the precise role of EFNA1 and its preferred receptor, EPHA2, is controversial. Several studies have found that EFNA1 may suppress EPHA2-mediated oncogenesis, or enhance it, depending on cell type and context. However, little is known about the conditions that influence whether EFNA1 promotes or suppresses tumorigenicity. EFNA1 exists in a soluble form as well as a glycophosphatidylinositol (GPI) membrane attached form. We investigated whether the contradictory roles of EFNA1 in malignancy might in part be related to the existence of both soluble and membrane attached forms of EFNA1 and potential differences in the manner in which they interact with EPHA2.</p> <p>Results</p> <p>Using a RNAi strategy to reduce the expression of endogenous EFNA1 and EPHA2, we found that both EFNA1 and EPHA2 are required for growth of HeLa and SK-BR3 cells. The growth defects could be rescued by conditioned media from cells overexpressing soluble EFNA1. Interestingly, we found that overexpression of the membrane attached form of EFNA1 suppresses growth of HeLa cells in 3D but not 2D. Knockdown of endogenous EFNA1, or overexpression of full-length EFNA1, resulted in relocalization of EPHA2 from the cell surface to sites of cell-cell contact. Overexpression of soluble EFNA1 however resulted in more EPHA2 distributed on the cell surface, away from cell-cell contacts, and promoted the growth of HeLa cells.</p> <p>Conclusions</p> <p>We conclude that soluble EFNA1 is necessary for the transformation of HeLa and SK-BR3 cells and participates in the relocalization of EPHA2 away from sites of cell-cell contact during transformation.</p
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Breast Tumor Stiffness and Bone Metastasis: How “Soil Selects Soil”
Breast cancer is the most common cancer amongst women globally and continues to produce considerable harm. The microenvironment of primary breast tumors plays a well-described role in promoting the growth and progression of the disease; however, despite our wealth of knowledge concerning how the biochemical and biophysical properties of primary tumors influence cancer cells in situ, very little is known about whether this influence persists after dissemination to metastatic sites, such as the skeleton. Bone metastases inflict the greatest morbidity associated with breast cancer, and they affect a majority of women with advanced disease. Although predictive gene signatures of osteolytic metastasis have been identified, their genesis remains obscure. Current models propose that bone metastases originate from rare subclones that arise stochastically during clonal evolution of primary tumors. In contrast, we reveal a deterministic origin of the osteolytic phenotype that lies in the response of breast cancer cells to mechanical stimuli in their primary microenvironment. Here, we show that primary tumor stiffness encodes a “mechanical memory” which instructs cancer cells to adopt and maintain distinct biophysical properties, in addition to promoting osteolytic bone metastasis. We present a “mechanical conditioning score” comprised of mechanically-regulated genes in order to proxy tumor stiffness response clinically, and we show that it is associated with bone-specific metastasis. Using a discovery approach, we trace mechanical memory to the mechanotransductive activation of RUNX2, an osteogenic gene bookmarker and bone metastasis driver. This combination of traits allows for the stable transactivation of osteolytic target genes which persists after cancer cells disseminate from their activating environment. Using genetic, epigenetic, and functional approaches, RUNX2-mediated mechanical memory can be simulated, repressed, selected, or extended. Taken together, these results show that the primary tumor microenvironment can determine the metastatic microenvironment, i.e. "soil selects soil."Dissertation not available (per author's request)Dissertation originally embargoed through 12/07/2019; contacted by author 7/1/2019 to place permanent restriction on dissertation. Kimberl