Dysregulation Of Lung Developmental Pathways Associated With Lkb1 Loss In Lung Cancer

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LALoss of the LKB1 tumor suppressor influences differentiation phenotypes in mouse models of lung adenocarcinoma and in human tumors. We utilize molecular data from resected human lung adenocarcinomas characterized by the TCGA to demonstrate that LKB1 deficient tumors exhibit a higher prevalence of neuroendocrine and gut-like differentiation markers than do LKB1 wild-type tumors (41% vs 9%, odds ratio = 7.3, P = 5.9E-19 for neuroendocrine differentiation; 36% vs 12%, odds ratio = 4.3, P = 2.5E-11 for gut-like differentiation. Fisheru0027s exact test). Using copy number analysis and transcription factor enrichment analysis, we link these phenotypes to activation of particular transcription factors, namely FOXA2, HNF1A, ASCL1, and TTF1. We observe similar associations among non-small cell lung cancer cell lines, which may represent appropriate ideal models for further experimentation. Furthermore, we examine these differentiation phenotypes using immunohistochemical analysis of a tissue microarray (TMA), combined with RNAseq expression analysis, and MS/MS proteomic characterization of the same cohort of 36 tumors. Our molecular characterization confirms the neuroendocrine and gut-like differentiation phenotypes observed in the TCGA dataset and their association with LKB1-loss. Moreover, our immunohistochemical analysis demonstrates that these distinct differentiation subtypes are heterogeneously expressed within single tumors. Co-expression of neuroendocrine, gut-like, and respiratory differentiation is significantly more likely to occur within LKB1 deficient tumors, and is also associated with increased expression of a c-Kit positive sub-population that appears to lack expression of more differentiated markers. Among the TCGA tumors, this tri-lineage expression pattern is seen in 12.5% of LKB1-deficient tumors, compared to 1% of LKB1-wild-type tumors (Odds ratio 11.5, P = 3.2E-8. Fisheru0027s exact test). These findings give further support to the role of LKB1 in regulating differentiation phenotypes in lung cancer, and may suggest a hierarchy of progenitor cells and lineage-specific subpopulations within these tumors.Citation Format: Jacob M. Kaufman, Cindy Lowe, Bradford Harris, Kelli Boyd, Joseph Amann, Rosana Eisenberg, David Carbone, Pierre Massion. Dysregulation of lung developmental pathways associated with LKB1 loss in lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2404.