Blood–Brain Barrier Remodeling in an Organ‐on‐a‐Chip Device Showing Dkk1 to be a Regulator of Early Metastasis

Abstract

Brain metastases are the most lethal progression events, in part because the biological processes underpinning brain metastases are poorly understood. There is a paucity of realistic models of metastasis, as current in vivo murine models are slow to manifest metastasis. Metabolic and secretory modulators of brain metastases utilizing two models consisting of in vitro microfluidic devices are delineated: 1) a blood–brain niche (BBN) chip that recapitulates the blood–brain‐ barrier and niche; and 2) a migration chip that assesses cell migration. Secretory cues provided by the brain niche that attract metastatic cancer cells to colonize the brain niche region are reported. Astrocytic Dkk‐1 is increased in response to brain‐seeking breast cancer cells and stimulates cancer cell migration. Brain metastatic cancer cells under Dkk‐1 stimulation increase gene expression of FGF‐13 and PLCB1. Further, extracellular Dkk‐1 modulates cancer cell migration upon entering the brain niche.

Understanding organotropism in cancer metastasis using microphysiological systems

“…Moreover, the microfluidic model simulating the brain-barrier niche, faithfully replicating the interplay between astrocytes and cancer cells constituting the BBB, unveiled the influence of gene expression associated with extravasation. 93 The localized degradation of the ECM and basement membrane, facilitated by the proteolytic arsenal of cancer cells, is a key aspect of breaching the BBB. For instance, silencing AKR1B10 in brain metastatic tumor cells suppressed their extravasation through the BBB in the in vitro Transwell model, in the ex vivo microfluidic chip, as well as the in vivo model of brain metastasis in nude mice (Fig.…”