Transmembrane Protease TMPRSS11B Promotes Lung Cancer Growth by Enhancing Lactate Export and Glycolytic Metabolism
Barrett L. Updegraff,
Xiaorong Zhou,
Yabin Guo,
Mahesh S. Padanad,
Pei-Hsuan Chen,
Chendong Yang,
Jessica Sudderth,
Carla Rodriguez-Tirado,
Luc Girard,
John D. Minna,
Prashant Mishra,
Ralph J. DeBerardinis,
Kathryn A. O’Donnell
Affiliations
Barrett L. Updegraff
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA
Xiaorong Zhou
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA; Department of Immunology, Nantong University School of Medicine, Nantong 226001, China
Yabin Guo
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
Mahesh S. Padanad
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA
Pei-Hsuan Chen
Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
Chendong Yang
Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Jessica Sudderth
Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Carla Rodriguez-Tirado
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA
Luc Girard
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA
John D. Minna
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA
Prashant Mishra
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Ralph J. DeBerardinis
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Kathryn A. O’Donnell
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA; Corresponding author
Summary: Pathways underlying metabolic reprogramming in cancer remain incompletely understood. We identify the transmembrane serine protease TMPRSS11B as a gene that promotes transformation of immortalized human bronchial epithelial cells (HBECs). TMPRSS11B is upregulated in human lung squamous cell carcinomas (LSCCs), and high expression is associated with poor survival of non-small cell lung cancer patients. TMPRSS11B inhibition in human LSCCs reduces transformation and tumor growth. Given that TMPRSS11B harbors an extracellular (EC) protease domain, we hypothesized that catalysis of a membrane-bound substrate modulates tumor progression. Interrogation of a set of soluble receptors revealed that TMPRSS11B promotes solubilization of Basigin, an obligate chaperone of the lactate monocarboxylate transporter MCT4. Basigin release mediated by TMPRSS11B enhances lactate export and glycolytic metabolism, thereby promoting tumorigenesis. These findings establish an oncogenic role for TMPRSS11B and provide support for the development of therapies that target this enzyme at the surface of cancer cells. : Updegraff et al. show that transmembrane protease TMPRSS11B is upregulated in lung squamous cell carcinoma, where it interacts with MCT4 and its obligate chaperone Basigin. TMPRSS11B catalytic activity promotes Basigin solubilization, which enhances lactate export and glycolytic metabolism, thereby promoting tumorigenesis. Keywords: TMPRSS11B, lung squamous cell carcinoma, MCT4, Basigin, lactate export, lung cancer, transmembrane serine protease, glycolytic metabolism, transposon mutagenesis, CRISPR-mediated genome editing
