Astrocyte-induced Reelin expression drives proliferation of Her2+ breast cancer metastases

Abstract

Breast cancer metastasis to the brain develops after a clinical latency of years to even decades, suggesting that colonization of the brain is the most challenging step of the metastatic cascade. However, the underlying mechanisms used by breast cancer cells to successfully colonize the brain's microenvironment remain elusive. Reelin is an archetypal extracellular glycoprotein that regulates migration, proliferation, and lamination of neurons. It is epigenetically silenced in various cancers, and its expression in multiple myelomas is linked to poor patient survival. We found that Reelin expression was low in primary breast cancer tissue. However, its expression was significantly higher in Her2 breast cancers metastasizing to the brain. In particular, Reelin was highly expressed in the tumor periphery adjacent to surrounding astrocytes. This augmented Reelin expression was seen in Her2 metastases, but not in triple negative (TN) primary tumors or in TN breast to brain metastasis cells co-cultured with astrocytes. Furthermore, the elevated expression was sustained in Her2 cells grown in the presence of the DNA methyltransferase inhibitor 5-azacytidine, indicating epigenetic regulation of Reelin expression. The relative growth and rate of spheroids formation derived from Her2 primary and BBM cells co-cultured with astrocytes were higher than those of TN primary and BBM cells, and knockdown of both Reelin and Her2 suppressed the astrocyte-induced growth and spheroid forming ability of Her2 cells. Collectively, our results indicate that within the neural niche, astrocytes epigenetically regulate Reelin expression and its interaction with Her2 leading to increased proliferation and survival fitness.

Polyunsaturated Fatty Acids from Astrocytes Activate PPARγ Signaling in Cancer Cells to Promote Brain Metastasis

“…On the other hand, most studies suggest prometastatic function for astrocytes. Astrocytes have been known to facilitate brain metastasis by increasing the survival, trans-BBB migration, and stemness of the invading cancer cells (12,24,(33)(34)(35)(36)(37), as well as by modulating the immune cells in the brain metastatic lesions (31,32). Here, we identified a proproliferative function of astrocytes by supplying unsaturated fatty acids to activate PPARγ signaling in the invading brain metastatic cancer cells (Fig.…”

“…Astrocytes have diverse functions in brain metastasis (12,24,(31)(32)(33)(34)(35)(36). On the one hand, activated astrocytes release the killing factor soluble FasL in the microenvironment to induce cancer cell death (12).…”

A Blazing Landscape: Neuroinflammation Shapes Brain Metastasis

“…This interaction may represent another aspect of cancer-induced astrogliosis and gliotic scar formation, physically ‘bridging’ between astrocytes and tumor cells. Once recruited and activated by brain metastasizing cells, astrocytes induce growth-promoting signaling in tumor cells (76,79).…”

Foe or friend? Janus-faces of the neurovascular unit in the formation of brain metastases

“…Expression of reelin, an extracellular neuronal protein, is induced by astrocytes only in Her2-positive, but not in triple negative breast cancer cells, leading to increased proliferation of Her2-positive cells in the brain environment. 160 Besides astrogliosis, microgliosis also starts already before extravasation. Tumor-associated microglia/ macrophages are predominantly resident microglia, but can also be monocytes/macrophages entering the brain from the bone marrow.…”