Investigating Phenotypic Changes in Response to Drug Treatments in Epithelial Ovarian Cancer Using a Novel Si-TiB2 Micropatterned Substrate



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Epithelial ovarian cancer (EOC) is one of the most prevalent cancers in women worldwide, with nearly 80% of cases diagnosed in late-stage of disease and an overall survival rate of less than 50%. 3D culture is necessary in order to study the in vivo response of cancer cells to therapeutic agents, in systems that better mimic innate cell-cell and cell-ECM interactions. This study evaluates the potential of a novel micropatterned substrate, fabricated using photolithography to deposit TiB2 micropatterns onto a Si wafer to study the response of EOC to epigenetic and chemotherapeutic drugs. Previous work has validated that the Si-TiB2 substrate enables selective deposition of growth factors and self-assembly of cells onto the TiB2 pattern through differences in stiffness, roughness, wetness, and charge gradient. For EOC cell lines, OVCAR3 (low invasiveness) and SKOV3 (high invasiveness), the Si-TiB2 micropatterned substrate supported cell proliferation and maintained viability, and 3D aggregation for SKOV3 cells. Treating SKOV3 aggregates and OVCAR3 monolayers on patterned substrates, with an epigenetic drug, vorinostat, also known as suberoylanilide hydroxamic acid (SAHA), resulted in decreased diameter and thickness, however viability of the remaining cells was unchanged. Genomic analysis of the treated aggregates suggests a change in phenotype of SKOV3 after treatment with SAHA. While studies show that SAHA alone may not be a sufficient treatment for EOC, it does have the potential to augment the treatment of some cancers when used in combination with chemotherapeutic agents. Treatment of SKOV3 aggregates with a combination of SAHA and Paclitaxel was shown to decrease proliferation and halt growth for an extended period after treatment however these results are not statistically different from the Paclitaxel treatment group, which agrees with a clinical trial of SAHA and Paclitaxel combinatorial treatment. Collectively, data support use of the micropatterned substrate for investigation of potential drug therapies for cancer treatment and cellular changes in response to drug treatment.



Tissue Engineering, Ovarian Cancer, 3D model, Substrate, Cell Biology