Abstract 5437: MESP1 cooperates with loss of ARF in malignant transformation

Cancer is a highly complex disease involving multiple genetic and epigenetic abnormalities. Inactivation or expression of key regulators can be critical for the maintenance and survival of tumor. My research aims at characterizing one such novel gene, Mesoderm Posterior Basic Helix-Loop-Helix transcription factor-1 (MESP1), in lung cancer initiation and progression. MESP1 is transiently expressed during embryonic development and is the first sign of nascent mesoderm. It is a master regulator of cardiovascular development. Our lab has discovered through genome-wide identification of MESP1 targets that it is required in mesendoderm lineage development. However, whether MESP1 plays any role in adult physiology, diseases and cancer, has never been investigated. The Cancer Genome Atlas (TCGA) data show that MESP1 expression is upregulated in cancers of all mesendoderm-derived tissues. Bioinformatic gene expression analysis of clinical lung adenocarcinoma patient samples (396) showed that MESP1 was highly overexpressed in lung cancer. Similarly, RT-qPCR analysis of patient RNA samples from various stages of lung cancer showed that MESP1 expression was induced in early stages of lung cancer. It was found that MESP1 stable overexpression in ARF-null MEFs leads to oncogenic transformation of cells. This was evidenced by changes in various hallmarks of cancer such as increased cell proliferation, colony formation and anchorage-independent growth (about 6-fold increase in no. of colonies per field). In order to determine if the MESP1-induced oncogenic transformation was p53 dependent, we overexpressed MESP1 in p53-null MEFs. Interestingly, we saw no significant change in cell proliferation, colony formation and anchorage-independent growth in MESP1-overexpressing p53 null MEFs, suggesting that these effects are p53-independent. Upon performing global transcriptomic analyses in MESP1-overexpressing ARF-null MEFs, we found that cell adhesion and cell migration were among the top pathways that were significantly altered. Future studies will focus on in vivo studies to check for effect of MESP1-overexpression and/or knockdown on tumor formation and investigate the mechanism of MESP1-induced oncogenic transformation linked with increased cellular adhesion and migration. Lung cancer is the leading cause of cancer-related deaths in both men and women. More than 50% of cases are diagnosed only at an advanced stage, for which the survival rate of the patient is only 4%. Hence, knowledge of new driver oncogenes of lung cancer is imperative. These results suggest that MESP1 plays an important role in cancer initiation and progression. Ultimately, this research would pave the way for therapeutic intervention of key processes regulated by MESP1 involved in lung cancer. Citation Format: Neha Tandon, Benjamin Soibam, Robert Schwartz, Yu Liu. MESP1 cooperates with loss of ARF in malignant transformation [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 5437.