AKR1B10 Promotes Brain Metastasis of Lung Cancer Cells in a Multi-Organ Microfluidic Chip Model

Abstract

Brain metastasis (BM) is a leading cause of mortality in patients with non-small cell lung cancer (NSCLC). However, the molecular mechanisms underlying BM of NSCLC remain largely unknown because we lack models to accurately investigate such a dynamic and complex process. Here we developed a multi-organ microfluidic chip and provided a new methodological platform to study BM. The chip consisted of two bionic organ units – an upstream “lung” and a downstream “brain” characterized by a functional “blood-brain barrier (BBB)” structure. The chip allowed real-time visual monitoring of the entire BM process, from the growth of primary tumor to its breaking through the BBB, and finally reaching the brain parenchyma. We verified this model using lung cancer cell lines with differing metastatic abilities. We first demonstrated that the protein expression of Aldo-keto reductase family 1 B10 (AKR1B10) was significantly elevated in lung cancer cell lines with higher metastatic ability and clinical brain metastases of lung cancers. Silencing AKR1B10 in brain metastatic tumor cells suppressed their extravasation through the BBB in the in vitro Transwell model and in our ex vivo microfluidic chip, as well as the in vivo model of metastasis to the brain in nude mice. Moreover, AKR1B10 downregulated the expression of matrix metalloproteinase (MMP)-2 and MMP-9 via MEK/ERK signaling in metastatic lung cancers. These data suggest that our multi-organ microfluidic chip is a practical alternative to study BM pathogenesis, and AKR1B10 is a potential diagnostic biomarker and a prospective therapeutic target for NSCLC BM.

Keywords: multi-organ microfluidic chip, lung cancer, brain metastasis, blood-brain barrier, AKR1B10