Abstract 4905: Novel gene expression profiles of poorly differentiated lung cancer are enriched in stem cell factors and predictive of worse clinical outcome

Poorly differentiated non-small cell lung cancer (NSCLC) at the histopathological level has been associated with shorter patient survival. Analogously, at the cellular level, poorly differentiated tumor cells exhibit more aggressive phenotypes than their well-differentiated counterparts, including higher tumorigenic potential and higher metastatic capacity. Effective therapeutic targeting of the malignant undifferentiated cells will require a deeper understanding of their molecular drivers. To investigate the hierarchical basis of heterogeneous NSCLC tumors, we developed an improved method to study the undifferentiated and differentiated states of primary tumor cultures. The cultures were established in defined serum-free media from freshly resected tumors and were induced to differentiate either by culture in serum-containing media or by exposure to the air-liquid interface (ALI) in serum-free media with two variations. Gene expression profiles revealed similar patterns of change in all three conditions, which confirmed the undifferentiated state of the initial culture; however, differentiation in serum caused many extraneous changes in gene expression, which suggested that the ALI method represents a more physiologically relevant condition. Gene Set Enrichment Analysis demonstrated that the profile of the undifferentiated state was enriched in signatures of embryonic stem cell factors, metastasis and drug resistance. In addition, novel gene expression signatures of the undifferentiated state were predictive of shorter patient survival in a clinical dataset of NSCLC. These results establish a robust method for studying the cellular hierarchy in NSCLC that is independent of cell surface markers, and the data reveal several potential avenues for future therapeutic intervention. Citation Format: Marc Isaac Damelin, Wenyan Zhong, Veronica K. Diesl, Maximillian T. Follettie, Kenneth G. Geles. Novel gene expression profiles of poorly differentiated lung cancer are enriched in stem cell factors and predictive of worse clinical outcome. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4905. doi:10.1158/1538-7445.AM2013-4905