Innovative 3D Cell Cultures Offer New Perspectives on Lung Cancer Treatment Resistance

Recent studies have demonstrated that using three-dimensional (3D) cell culture models significantly enhances our understanding of how lung cancer responds to therapy, especially emphasizing the role of the protein YAP in treatment resistance. Researchers have shown that YAP's activity varies markedly depending on whether cancer cells are grown in traditional two-dimensional (2D) monolayers or in more realistic 3D spheroid structures that better mimic the tumor's natural environment.

In experiments conducted on human non-small cell lung cancer (NSCLC) cells, scientists implanted these cells in mice and treated them with the EGFR inhibitor afatinib. Post-treatment analysis revealed that while most tumor cells were eliminated, a small population of drug-tolerant persister cells (DTPs) survived and exhibited nuclear YAP activation, a key factor promoting survival and resistance. Immunofluorescence microscopy confirmed this relocation of YAP to the nucleus in DTPs, indicating its role in mediating resistance.

The team further compared cell cultures grown in flat monolayers versus spheroids. They found that monolayer cultures retained active EGFR signaling and nuclear YAP localization, which correlated with resistance to treatment, whereas spheroid cultures showed reduced EGFR activity and cytoplasmic YAP, making the cells more susceptible to drug-induced death. This suggests that 3D spheroids, by more accurately reflecting tumor architecture, provide a better model for studying drug responses.

Extending their research to other cancer types and treatments, the scientists observed that in five of six cases, cells grown as spheroids were significantly more sensitive to targeted therapies than those in monolayer cultures. Moreover, when cells were engineered to overexpress a mutated, nuclear-localized form of YAP, they demonstrated increased survival during drug treatment, confirming YAP’s critical role in non-genetic resistance mechanisms.

Lead researcher Andrei Goga emphasized that traditional 2D cultures might underestimate resistance driven by factors like YAP activity. The findings advocate for incorporating 3D models in preclinical testing to better predict patient responses and to explore combination therapies that target YAP alongside standard treatments. These insights could pave the way for more effective strategies to overcome resistance in lung and other cancers.

This pioneering work underscores the importance of tumor architecture in drug resistance and highlights YAP as a promising therapeutic target. Future studies are needed to optimize timing and combination of YAP inhibitors to enhance treatment outcomes.

Source: https://medicalxpress.com/news/2025-04-3d-cell-cultures-insights-lung.html