Lung cancer is the leading cause of cancer death and is estimated to claim over 160,000 lives in the United States in 2008;thus, the study of lung tumor cell biology is critical for discovering novel targets to treat the disease. Recent evidence suggests that solid tumors comprise a small fraction of lung cancer stem cells that seed the tumor bulk and may be responsible for metastases and resistance to therapy. The mechanisms regulating how lung cancer stem cells undergo self-renewal and maintain tumor growth are unknown. In recent experiments, it was determined that a small fraction of lung cancer cells asymmetrically divide their template DNA, and that the process is abrogated by Notch pathway inhibitors. This finding has broad implications in normal and tumor cell homeostasis research. The central hypothesis of this proposal is that Notch signaling regulates the lung cancer stem cell pool by maintaining a dynamic balance between asymmetric and symmetric divisions. The objectives are to determine if asymmetrically dividing lung cancer cells are restricted to the cancer stem cell fraction and if Notch signaling regulates asymmetric cell division in lung cancer. The first specific aim to achieve these objectives is to study asymmetric cell division as a fundamental mechanism restricted to the lung CSC pool.
The second aim i s to investigate canonical Notch signaling as a regulator of asymmetric cell division and CSC self-renewal in lung cancer. This will be achieved by expression analysis of Notch pathway genes in asymmetrically dividing human lung cancer cells, and targeting of identified proteins for disruption of asymmetric cell division and alterations in self-renewal. The rationale of the proposed research is that, once it is known that self-renewal of the CSC pool is regulated by mechanisms that control asymmetric division, those pathways can later be targeted pharmacologically by new and innovative approaches in the treatment of lung cancer.

Public Health Relevance

Cancer of the lung is the leading cause of cancer deaths in the United States. For several decades, there has been limited improvement in lung cancer survival that is attributed to early detection or targeted therapy, and the five-year survival rate hovers at a meager 15-20%. Studies aimed at unraveling the fundamental properties governing how lung tumors are maintained may lead to novel and more efficacious therapies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Career Transition Award (K22)
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Subcommittee G - Education (NCI)
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Jakowlew, Sonia B
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University of Medicine & Dentistry of NJ
Internal Medicine/Medicine
Schools of Medicine
United States
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Morgan, Katherine M; Fischer, Bruce S; Lee, Francis Y et al. (2017) Gamma Secretase Inhibition by BMS-906024 Enhances Efficacy of Paclitaxel in Lung Adenocarcinoma. Mol Cancer Ther 16:2759-2769
Liu, Wenyu; Morgan, Katherine M; Pine, Sharon R (2014) Activation of the Notch1 Stem Cell Signaling Pathway during Routine Cell Line Subculture. Front Oncol 4:211
Capaccione, Kathleen M; Hong, Xuehui; Morgan, Katherine M et al. (2014) Sox9 mediates Notch1-induced mesenchymal features in lung adenocarcinoma. Oncotarget 5:3636-50
Mondal, Abdul M; Horikawa, Izumi; Pine, Sharon R et al. (2013) p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes. J Clin Invest 123:5247-57
Liu, Wenyu; Jeganathan, Gajan; Amiri, Sohrab et al. (2013) Asymmetric segregation of template DNA strands in basal-like human breast cancer cell lines. Mol Cancer 12:139
Patel, Shyam A; Ramkissoon, Shakti H; Bryan, Margarette et al. (2012) Delineation of breast cancer cell hierarchy identifies the subset responsible for dormancy. Sci Rep 2:906