Various cancer metastasis models based on organ-on-a-chip platforms have been established to study molecular mechanisms and screen drugs. However, current platforms can neither reveal hypoxia-induced cancer metastasis mechanisms nor allow drug screening under a hypoxia environment on a multiorgan level. We have developed a three-dimensional-culture multiorgan microfluidic (3D-CMOM) platform in which the dissolved oxygen concentration can be precisely controlled. An organ-level lung cancer and liver linkage model was established under normoxic/hypoxic conditions. A transcriptomics analysis of the hypoxia-induced lung cancer cells (A549 cells) on the platform indicated that the hypoxia-inducible factor 1α (HIF-1α) pathway could elevate epithelial-mesenchymal transition (EMT) transcription factors (Snail 1 and Snail 2), which could promote cancer metastasis. Then, protein detection demonstrated that HIF-1α and EMT transcription factor expression levels were positively correlated with the secretion of cancer metastasis damage factors alphafetoprotein (AFP), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (γ-GT) from liver cells. Furthermore, the cancer treatment effects of HIF-1α inhibitors (tirapazamine, SYP-5, and IDF-11774) were evaluated using the platform. The treatment effect of SYP-5 was enhanced under the hypoxic conditions with fewer side effects, similar to the findings of TPZ. We can envision its wide application in future investigations of cancer metastasis and screening of drugs under hypoxic conditions with the potential to replace animal experiments.

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Fine particulate matter (PM2.5)-induced metabolic diseases have attracted a great deal of attention recently. However, the relevant metabolic mechanisms of PM2.5 in vivo have not yet been fully described due to the lack of reliable platforms. Herein, a membrane-free liver-gut-on-chip (L-GOC) platform was developed to investigate metabolism dysregulation induced by PM2.5. A multiple organ system with a liver–gut structure and two circulation paths (L-G and G-L circulation paths) was created, and then cells were exposed to PM2.5 on this platform. Secreted high-density lipoprotein (HDL) levels were detected, which demonstrates that this multiple organ system functioned with normal physiological metabolism at the organ level. Untargeted metabolomic analysis showed that there were 364 metabolites of LO2 cells dysregulated after exposure to PM2.5 at a concentration of 200 μg/mL. Moreover, cholesterol and bile acid metabolism were significantly dysregulated. Further immunofluorescence and ELISA assays confirmed that signal transduction pathways related to cholesterol metabolism (LCAT–CE, PON1–HDL, and SRB1–HDL metabolic pathways) and bile acid metabolism (CYP7A1–CA/CDCA/DCA metabolic pathways) were disturbed. These results indicate that PM2.5 primarily disturbed cholesterol metabolism of the liver and then disrupted bile acid metabolism of the liver (primary bile acid biosynthesis) and gut (secondary bile acid biosynthesis) via related metabolic pathways. These findings may partially explain the metabolic mechanisms of cells triggered by PM2.5 exposure.

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