Thoracic malignancies account for more deaths than prostate, breast and colorectal cancer combined. The most frequent lung cancer subtype is lung adenocarcinoma (LUAD), which is initiated in the peripheral airways and can disseminate rapidly to other vital organs. There are currently no effective therapeutics for metastatic LUAD, which are biologically and genetically diverse. In addition, recent genomic re-sequencing efforts have revealed thousands of new human gene loci that, despite not coding for any proteins, may be critical to human medicine. Given the heterogeneity and genetic complexity of LUADs, a multi-disciplinary approach is needed to understand the molecular pathogenesis of lung cancer metastasis and uncover novel mediators and biomarkers of this disease. Through computational and experimental approaches, we examined the molecular relationship between cell differentiation states, lung cancer subtypes, and clinical outcome, to discover a role for cel lineage- restricted genes in metastatic LUAD. These alterations include changes in the transcription of novel long intergenic non-coding RNAs (lincRNAs) with unknown function. In particular, we identified one lincRNA, referred to here as linc-XIM (X-linked inhibitor of metastasis), as a potential suppressor of metastasis and biomarker of epigenetic abnormalities specifically in human LUADs. We posit that linc-XIM inhibits metastasis by antagonizing the activity of the Polycomb repressor complex 2 (PRC2) and/or its recruitment to relevant genomic targets. Thus, repression of linc-XIM may enhance metastatic competence of LUADs by epigenetically reprogramming the transcriptome of indolent LUAD cells. We will test this hypothesis by first characterizing the biological function(s) of linc-XIM during lung LUAD differentiation, tumor growth and distant organ metastasis, using our established in vivo model of metastatic dissemination and colonization by human LUAD cells. We will employ genetic and pharmacological approaches that enable temporally controlled gain and loss of function, to establish the functional association between linc-XIM expression and PRC2 activity. In parallel to these biological experiments, we will combine molecular, biochemical, and in situ techniques to elucidate the mechanism by which linc-XIM sequesters or inhibits PRC2 protein subunits and ultimately regulates epigenetic silencing. Finally, we will examine the correlation between the expression of linc-XIM, PRC2 subunits, PRC2 target genes, and clinical outcome in human LUAD biospecimens. The overall goal of our application may therefore shed new light into the role of tissue specific lincRNAs in cancer progression, and provide insights into more effective epigenetic therapies for lung cancer patients at risk for metastatic disease.

Public Health Relevance

Metastatic lung cancer is the principal source of cancer related deaths, and yet the molecular causes of this disease remain unknown. Our novel multi-disciplinary approach will identify new large genes that, despite not coding for any proteins, can promote the metastatic spread of specific forms of human lung cancer. This innovative application will also help tailor emerging therapeutics to treat lung cancer patients at risk of metastatic disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZCA1-SRLB-1 (M1))
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Ault, Grace S
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Yale University
Schools of Medicine
New Haven
United States
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