A microfluidic demonstration of ?cluster-sprout-infiltrating? mode for hypoxic mesenchymal stem cell guided cancer cell migration

Mesenchymal stem cells (MSCs) play a critical role in tumor metastasis. However, the dynamic process of MSCsmediated cancer cell invasion remains inconclusive. In breast cancer mouse models, we observed that MSCs promoted lung metastasis. We constructed a microfluidic-based 3D co-culture device to monitor MSCs-mediated cancer cell invasion in a nutrient-deficient hypoxic microenvironment. On biomimetic microfluidic devices, MSCs guided cancer cell migration in a cluster-sprout-infiltrating mode. Importantly, hypoxic conditions significantly promoted MSCs migration at the infiltration stage, leading to accelerated breast cancer cell invasion. Moreover, hypoxia related LncRNA analysis showed that H19 was dramatically upregulated in response to hypoxic conditions. Conversely, H19 depletion impaired MSCs-directed breast cancer cell invasion. Mechanistically, H19 functions as a competitive endogenous RNA (ceRNA) which sequesters miRNA let-7 to release its target matrix metalloproteinase-1 (MMP1). Intriguingly, aspirin dramatically suppressed H19 and MMP1 expression and blocked MSCs infiltration under hypoxic conditions, resulting in alleviated breast cancer cell invasion. These findings point to the metastatic promoting role of MSCs in tumor stroma and suggest that MSCs might be a therapeutic target for metastatic breast cancer.

Automated summary

Mesenchymal stem cells (MSCs) play a critical role in promoting tumor metastasis, particularly in breast cancer. Through the use of a microfluidic-based 3D co-culture device, it was observed that MSCs guide cancer cell migration and accelerate invasion in a hypoxic microenvironment. The upregulation of H19 under hypoxic conditions was found to be important in MSCs-mediated cancer cell invasion. Aspirin was shown to suppress H19 expression and inhibit MSCs infiltration, leading to reduced breast cancer cell invasion.