Cancer-metastasis-on-a-chip reveals efficacy of bevacizumab and siRNA in overcoming carboplatin resistance in SKOV3 ovarian cancer within a fibrotic metastatic microenvironment.

Microfluidic platforms have emerged as powerful tools for investigating complex interactions between cells and their microenvironment. Conventional in vitro cancer models often fail to accurately replicate the complexities of the in vivo tumor microenvironment. In contrast, cancer-metastasis-on-a-chip models integrate the benefits of three-dimensional cell cultures with microfluidic technology, providing more physiologically relevant platforms for studying cancer biology and improving precision of drug screening. These platforms enable the compartmentalization of the metastatic cascade, allowing for more detailed understanding of its fundamental mechanisms. In this study, we employed an advanced microfluidic cancer-on-a-chip model to examine the invasion dynamics of SKOV3 ovarian cancer cells under fibrotic conditions. Specifically, we assessed the therapeutic efficacy of bevacizumab in combination with siRNA targeting ROBO1, LCP1, and GATA3-genes previously identified as upregulated and implicated in enhanced invasion during the progression from non-resistant (Non-R) SKOV3 to carboplatin-resistant (Carbo-hR) variants. Our results demonstrated a modest increase in invasive behavior in Non-R SKOV3 cells within the fibrotic microenvironment. In contrast, Carbo-hR cells exhibited dramatically increased invasion and a strong metastatic affinity for fibrotic lung tissue. Monotherapy with bevacizumab showed limited efficacy in Carbo-hR cells compared to non-R cells. However, the combined treatment with bevacizumab and siRNA targeting ROBO1, LCP1, and GATA3 substantially suppressed the invasive capacity of Carbo-hR cells, effectively restoring their phenotype to that of non-R cells. These findings highlight the promise of combining anti-angiogenic agents with targeted gene silencing strategies to overcome drug resistance and inhibit metastasis, particularly within fibrotic tumor microenvironments.