Tumors frequently enlist developmental genes to translate oncogenic signals into drivers of tumor progression. To gain a better understanding of the molecular mechanisms behind lung carcinogenesis and progression, we are focusing on the potential role of Sox9, a transcription factor required for human development. We found that Sox9 is barely expressed in normal lung tissue, but is overexpressed in primary human and murine lung tumors as well as lung cancer cell lines. We determined that Sox9 is not only a direct target gene of Notch1 signaling, but it is also a key mediator of Notch1-induced mesenchymal-like cellular morphological changes, E- cadherin repression, cell motility, and invasion in lung cancer. Our studies suggest that Sox9 is downstream of other oncogenic pathways. We propose that Sox9 is a terminal hub for convergence of upstream oncogenic signals, and plays a central role in mediating their contribution to lung tumorigenesis and progression. Therefore, targeting Sox9 expression could alleviate the resistance often invoked by redundant oncogenic pathways during treatment with targeted therapies. The overall goals of this proposal are to validate the pathways regulating Sox9 expression and mediating Sox9's role in the induction of cell motility and invasion. We will test the function of Sox9 during murine lun carcinogenesis. Using patient-derived lung tumor xenografts and a validated platform to target Sox9 in vivo, we will test if Sox9 repression has anti-tumor activity. This study will help in understanding the regulation of lung tumor progression by a novel embryonic developmental gene and develop a strategy for potentially circumventing therapeutic resistance.

Public Health Relevance

Expression of the Sox9 developmental gene in lung cancer correlates with tumor progression and poor survival. This proposal takes a comprehensive approach to understand how Sox9 expression is regulated and how Sox oversees lung tumorigenesis and tumor progression. Successful completion of this project may translate into a new therapeutic strategy for lung cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA190578-03S1
Application #
9479728
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Ault, Grace S
Project Start
2014-09-19
Project End
2019-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Rbhs -Cancer Institute of New Jersey
Department
Type
Overall Medical
DUNS #
078728091
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Pine, Sharon R; Sabaawy, Hatem E (2018) Editorial: Harnessing the Power of Patient Derived Models of Cancer. Front Oncol 8:349
Patrizii, Michele; Bartucci, Monica; Pine, Sharon R et al. (2018) Utility of Glioblastoma Patient-Derived Orthotopic Xenografts in Drug Discovery and Personalized Therapy. Front Oncol 8:23
Pine, Sharon R (2018) Rethinking Gamma-secretase Inhibitors for Treatment of Non-small-Cell Lung Cancer: Is Notch the Target? Clin Cancer Res :
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
Morgan, Katherine M; Riedlinger, Gregory M; Rosenfeld, Jeffrey et al. (2017) Patient-Derived Xenograft Models of Non-Small Cell Lung Cancer and Their Potential Utility in Personalized Medicine. Front Oncol 7:2
Hong, Xuehui; Liu, Wenyu; Song, Ruipeng et al. (2016) SOX9 is targeted for proteasomal degradation by the E3 ligase FBW7 in response to DNA damage. Nucleic Acids Res 44:8855-8869