Abstract 1135: SOX9 regulates cancer stem-like cells and chemotherapy response in non-small cell lung cancer

Abstract Lung cancer is the leading cause of cancer-related death worldwide in both men and women. A major limitation of the lung cancer chemotherapy effectiveness is drug resistance and tumor relapse, which both have been attributed to the acquisition of cancer stem-like cells (CSCs). Thus, it is crucial to identify specific markers and drug targets for this cell population. Our work is focused on the embryonic transcription factor SOX9, which has been implicated in CSC regulation in a number of cancer types, but little is known about its role in non-small cell lung cancer (NSCLC), the predominant type of lung cancer. In addition, the regulatory mechanisms and downstream targets of SOX9 as well as its role in chemoresistance are largely unknown. We hypothesized that SOX9 plays a key role in lung cancer progression and chemoresistance by stimulating cancer stem-like properties. To test this hypothesis, we genetically manipulated SOX9 expression in various NSCLC cell lines and evaluated its effects on CSC formation, biomarkers expression, and drug resistance. Our results showed that SOX9 depletion decreases the number of tumor spheres formed by NSCLC cells, thus supporting its role in CSC regulation in lung cancer. We also showed that SOX9 depletion dramatically downregulates the expression of a functional CSC regulator ALDH1A1. Consistent with this finding, SOX9 overexpression in non-cancer lung epithelial cells promotes tumor sphere formation. Moreover, we noticed that SOX9 expression goes up in response to chemotherapy exposure. Notably, SOX9 knockdown increases cell sensitivity to the chemotherapeutic cisplatin, whereas SOX9 overexpression decreases it. Depletion of SOX9 also increases CSC sensitivity to cisplatin, as demonstrated by the tumor sphere formation assay. Analysis of the Cancer Genome Atlas (TCGA) data showed that high SOX9 expression correlates with poor survival in NSCLC patients. Taken together, our results indicate the essential role of SOX9 in the regulation of CSCs in NSCLC. Since CSCs are a key driver of chemoresistance and relapse, our findings may have important implications in the development of novel therapeutic strategies for chemoresistant and recurrent lung cancer. Citation Format: Maria Voronkova, Sudjit Luanpitpong, Yon Rojanasakul. SOX9 regulates cancer stem-like cells and chemotherapy response in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1135.