UT Southwestern researchers have found that an enzyme on the surface of some lung cancer cells helps feed the cancer, making it a tempting treatment target. The enzyme, transmembrane serine protease 11B (TMPRSS11B) is described in a report published today in the journal Cell Reports. In addition to being found in squamous cell lung cancer and prostate cancer, the enzyme also has been identified in squamous cell head, neck, and cervical cancers, said Dr. Kathryn O’Donnell, Assistant Professor of Molecular Biology and her team identified TMPRSS11B while searching for genes that can convert precancerous lung cells into malignant cells that can form tumors. In this study, researchers found that the enzyme strongly promoted the growth of certain types of lung cancer cells. They basically uncovered a new mechanism that expands our understanding of how cancer cells reprogram their metabolism to provide energy for rapid growth as they form tumors.
The researchers noticed that the enzyme was expressed at increased levels in human squamous cell lung cancers – a common type of non-small cell lung cancer – and that suppressing the levels of TMPRSS11B through gene editing or RNA interference reduced tumor growth in mouse models. The research focused on TMPRSS11B’s ability to encourage the movement of lactic acid, a byproduct of glucose metabolism long thought to be a waste product. It derives from glycolysis, the main metabolic pathway cells use to produce energy from glucose; this same pathway is highly active in most types of cancer cells. Groundbreaking research last year from UT Southwestern Professor Dr. Ralph DeBerardinis’ laboratory found that, in fact, lactate provides fuel for growing tumors. Dr. DeBerardinis, a co-author on the current study, is Chief of the Division of Pediatric Genetics and Metabolism at UT Southwestern, Professor at the Children’s Medical Center Research Institute at UT Southwestern.
The study describes how TMPRSS11B helps two other cell proteins – Basigin and MCT4 – move lactate out of cancer cells to promote tumor growth. MCT4 is actually a lactate transporter, a channel specifically purposed to move lactate inside cells. Tumors make and consume large quantities of lactate; transport of this nutrient impacts disease progression in lung cancer. Well, the team found that some lung tumors enlist the help of TMPRSS11B to assist in lactate transport to facilitate tumor growth. Dr. O’Donnell also pointed out that TMPRSS11B sits on the cancer cell’s surface, where it acts as an enzyme encouraging lactate export, making it a possible target for antibody or small molecule therapy. Her lab will next perform more detailed studies to better understand how the enzyme promotes lactate export and begin to explore strategies to inhibit TMPRSS11B for therapeutic purposes.
Dr. O’Donnell explained on the findings: “Because most healthy cells appear to lack TMPRSS11B, a treatment that targets the protein may have fewer toxic side effects in cancer patients. In addition to providing fuel, it is thought that lactate can suppress the immune system. Investigating whether this enzyme can influence the immune system’s ability to attack tumors will be an important direction for future research. In TMPRSS11B, we have the perfect cancer drug target: it’s accessible on the tumor cell surface, it’s selective for cancer cells, blocking it both inhibits the cancer growth and sets the stage for developing better immunity against the cancer, and its presence makes it a diagnostic for which patients to treat”.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Apicella M et al. Cell Metab. 2018 Dec 4; 28(6):848-865.
Updegraff BL et al. Cell Rep. 2018 Nov 20; 25(8):2223-33.
Hui S et al. Nature. 2017 Nov 2; 551(7678):115-118.
Feng J et al. Oncogene. 2017 Oct 19; 36(42):5829-5839.