Targeting a Novel Cell Surface Serine Protease for Lung Cancer Therapy
Abstract
Lung cancer is the leading cause of cancer deaths worldwide and is caused by mutations in DNA that promote uncontrolled cell growth or inappropriate cell survival. We developed a powerful method that creates specific mutations in DNA of human cells growing in the laboratory. Mutagenized cells are assayed for the ability to form colonies in soft agar (a hallmark of cancer cells) or implanted into mice and assayed for their ability to form tumors. After isolating DNA from colonies or tumors, we can identify the genes that have been altered, thus revealing their cancer-promoting properties. We applied this strategy to human lung epithelial cells with the goal of discovering new driver genes that promote lung cancer. Among the genes we identified in this screen was TMPRSS11B, which encodes a cell surface protein. TMPRSS11B is present at higher levels in lung squamous carcinoma cells compared to normal lung epithelial cells, and high TMPRSS11B levels correlates with poor survival of lung cancer patients. We demonstrated that elevating or reducing TMPRSS11B levels in human lung cancer cells strongly potentiates or inhibits their tumor-forming ability, respectively. Moreover, TMPRSS11B enhanced the efficacy of lactate export, thereby promoting glycolytic flux and tumor growth. There has been a resurgence of interest in lactate transport and metabolism, given the discovery that this metabolite serves as a fuel in normal tissue and in cancer. These studies suggest that manipulation of lactate production or transport is a vulnerability that may be exploited for therapeutic targeting of lung cancer cells. Experiments in this application will validate TMPRSS11B as a therapeutic target and elucidate the mechanisms through which this cell surface protein promotes lactate export and tumorigenesis. This proposal addresses the following Areas of Emphasis: (1) understand the molecular mechanisms of progression to clinically significant lung cancer and (2) identify innovative strategies for lung cancer treatment. We hypothesize that TMPRSS11B-mediated tumor cell lactate secretion acidifies the tumor microenvironment and impairs T cell function. Successful completion of these studies will provide a better understanding of how TMPRSS11B inhibition impacts immune cell function alone and in combination with immune checkpoint inhibitors. These studies will also provide a clear experimental foundation for the development of individualized treatment based on targeting TMPRSS11B or lactate export pathways, including monoclonal antibodies and small molecular inhibitors. It is anticipated that development of lactate transport inhibitors may facilitate rapid initiation of lung cancer clinical trials. This may ultimately benefit and lead to cure for military patients with lung cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010539
Entities
People
- Kathryn O Donnell
Organizations
- United States Army
- University of Texas Southwestern Medical Center