Non-small cell lung carcinoma (NSCLC) is highly correlated with smoking and smokers constitute about 75% of NSCLC patients. Many tobacco-specific carcinogens present in cigarette smoke cause DNA damage, leading to the mutation of vital genes like Ras, p53 and Rb. In addition, many of these tobacco carcinogens as well as nicotine itself can promote cell proliferation and angiogenesis through the activation of nicotinic acetylcholine receptors (nAChRs). NSCLC in smokers and non-smokers are qualitatively different and have different molecular signatures;for example, cancers in non-smokers predominantly have mutations in the kinase domain of EGFR. There are also histological distinctions between NSCLC in smokers and non-smokers, the former being predominantly squamous cell carcinomas and the latter mainly adenocarcinomas. Nevertheless, NSCLC in both the groups of patients are highly metastatic, leading to mortality. Given the fact that the primary cells of the lung that give rise to these tumors can proliferate in response to signals transduced through nicotinic acetylcholine receptors as well as EGFR, and since tumor cells derived from these tissues actively divide and invade in response to nAChR and EGFR signaling, we hypothesize that there might be common mediators of these signals in smokers and non-smokers. Specifically, we propose that the helix-loop- helix protein Id1 is a common mediator of proliferation, invasion and angiogenesis in NSCLC in smokers and non-smokers. Id1 is known to play a significant role in the progression and metastasis of a variety of tumors, including those of breast, prostate and pancreas;at the same time, little is known about its potential role in the biology of NSCLC. Our preliminary data shows that Id1 is induced in NSCLC cells in response to nAChR as well as EGFR signaling and that depletion of Id1 prevents nicotine and EGF-induced proliferation and invasion. Depletion of Id1 also greatly reduced nicotine and VEGF-induced angiogenic tubule formation in matrigel. Further, Id1 was elevated in human NSCLC samples, with maximal amount present in metastatic tumors. We hypothesize that both nAChRs and EGFR induce Id1 in a Src and STAT3-dependent fashion and contributes to the invasive and metastatic properties of these cancers. Based on these observations, we propose three specific aims: (1) To assess whether Id1 is a common mediator of NSCLC growth in response to nicotinic receptor and EGFR signaling (2) To evaluate the role of Id1 in nAChR-induced angiogenesis and metastasis (3) To evaluate the contribution of Id1 to the growth and metastasis of NSCLC in smokers and non-smokers and to assess whether elevated Id1 correlates with poor prognosis. We believe that these studies will identify novel pathways that are involved in the genesis and progression of non-small cell lung cancers and will lead to the development of novel therapeutic agents to combat this disease.

Public Health Relevance

Non-small cell lung cancer is mainly caused by cigarette smoking and 75% of patients are smokers. At the same time, only about 10-20% of smokers are afflicted with NSCLC. On the other hand, 25% of NSCLC patients are non-smokers. The disease in smokers and non-smokers show many differences as well as commonalities. We hypothesize that even though NSCLC in smokers and non-smokers are caused by mutation of different genes, there may be common signaling molecules that facilitate the growth and metastatic spread of these tumors. We propose to study one such molecule, Id1, which is strongly correlated with the metastatic spread of other types of cancers. We believe that an in-depth mechanistic analysis as proposed in this application will lead to the development of novel therapeutic agents for non-small cell lungs cancer based on targeting the Id1 protein.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Tumor Progression and Metastasis Study Section (TPM)
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Johnson, Ronald L
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H. Lee Moffitt Cancer Center & Research Institute
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Bora-Singhal, Namrata; Nguyen, Jonathan; Schaal, Courtney et al. (2015) YAP1 Regulates OCT4 Activity and SOX2 Expression to Facilitate Self-Renewal and Vascular Mimicry of Stem-Like Cells. Stem Cells 33:1705-18
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