Abstract 2645: Rnd3 depletion in lung cancer cell lines decreases cell invasion and migration in a ROCK1 independent manner

Abstract The purpose of this study is to investigate how altered expression levels of the small Rho GTPase, Rnd3, affects lung cancer cells. Lung cancer is among the most common and deadliest forms of cancer in the US. Most lung cancers metastasize, with lung to brain metastasis being the number one killer of lung cancer patients. Studying mechanisms that drive metastatic potential is key to unlocking new strategies for the treatment of this deadly form of cancer. Our focus for this study is Rnd3, an atypical GTPases, which has roles in regulating proliferation and cell migration in other cancer types. Our analysis of The Cancer Genome Atlas data predicts that lung adenocarcinoma patients with low levels of Rnd3 have significant higher survival rate. We investigated the role of Rnd3 by depleting its expression in the lung adenocarcinoma cell line (A549), and also patient-derived lung to brain metastasis (PDLBM) cell lines (601 and 620) as a proxy for advance disease. We observed no significant difference in cell viability or cell cycle progression between Rnd3-depeled and control groups. We did observe a significant effect on cell invasion and migration, Rnd3 depletion significantly decreases cell invasion and migration across all three tested cell lines. Previous studies on Rnd3 in melanoma cells found that Rnd3 signals via the RhoA-ROCK1 pathway, which impacts cell adhesion and the actin cytoskeleton, ultimately regulating cell invasion. However, when we either chemically inhibited ROCK1 or knocked down ROCK1 expression in our lung adenocarcinoma and PDLBM cells, it did not rescue the invasive phenotype. Our findings indicate that Rnd3 regulates cell invasion and migration, two hallmarks of metastasis, in lung cancer via a distinct pathway, independently from ROCK1. Identifying this novel mechanism will provide crucial insights for developing treatment for lung cancer metastasis. Citation Format: Noemi Garcia Garcia, Thanh Ha Vy Nguyen, Dane Richey, Cody Ashby, Analiz Rodriguez, Katie R. Ryan. Rnd3 depletion in lung cancer cell lines decreases cell invasion and migration in a ROCK1 independent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2645.