Transmembrane Protease TMPRSS11B Promotes Lung Cancer Growth by Enhancing Lactate Export and Glycolytic Metabolism

Abstract

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