Abstract A41: SOX11 transcriptionally regulates a cytokine-based gene signature in lung cancer-associated fibroblasts (LCAF) to promote tumor growth

Abstract

Abstract Increasing evidence points to an important role for the tumor microenvironment in cancer progression. However, the role of tumor stroma in the pathogenesis of lung cancer is poorly understood. Desmoplasia is a common pathologic feature of many NSCLC. We noted a similar phenotype in a mouse model of lung cancer driven by expression of oncogenic Kras. Lung cancer-associated fibroblasts (LCAFs) and normal lung fibroblasts (NLFs) from the mouse model of Kras-driven lung cancer were isolated and queried at the functional level using a xenograft model. First, we observed that LCAFs promote tumor growth more favorably than NLFs in vivo when co-injected with mouse tumor cells. Moreover, NLFs passaged in vivo acquire features of LCAFs as indicated by an increased tumor-promoting capacity on mouse and human NSCLC xenografts. In addition, conditioned media from LCAFs stimulated cell proliferation in vitro more significantly than that of NLFs. Expression profiling of NLFs and LCAFs using microarrays uncovered a gene set that includes multiple secreted proteins and genes related to inflammatory processes. Moreover, the SRY-related HMG transcription factor Sox11 was highly up-regulated in LCAFs compared to NLFs. Over-expression and knock-down experiments have confirmed that Sox11 regulates the expression of many of the secreted proteins expressed in LCAFs. The relevance of these findings for human NSCLC is suggested by the observation that the mouse LCAF gene expression signature was predictive of survival in a large cohort of human NSCLC. Besides, Sox11 and several of the secreted proteins expressed in LCAFs, along with their putative receptors, were up-regulated in human NSCLC samples. In conclusion, we have identified a potentially novel regulator of the transition between NLFs and LCAFs and, thus, uncovered a new signaling hub that could be used for therapeutic intervention.