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

Pathways underlying metabolic reprogramming in cancer remain incompletely understood. We identified the Transmembrane Serine Protease TMPRSS11B as a novel gene that promotes transformation of immortalized human bronchial epithelial cells. TMPRSS11B is upregulated in human lung squamous cell cancers and high expression is associated with poor survival of non-small cell lung cancer patients. TMPRSS11B depletion in human lung squamous cell cancer reduced transformation and tumor growth. TMPRSS11B harbors an extracellular protease domain and we hypothesized that catalysis of a membrane bound substrate modulates tumor progression. Interrogation of a set of soluble receptors revealed that wild-type, but not catalytic mutants of TMPRSS11B promotes membrane release of Basigin, an obligate chaperone of the lactate monocarboxylate transporters MCT1 and MCT4. To investigate whether TMPRSS11B regulates lactate transport, we monitored intracellular lactate content and lactate secretion. Our data suggest TMPRSS11B regulates cellular lactate levels by interacting and co-localizing with Basigin and MCT4 at the plasma membrane to enhance their lactate export efficiency. Specifically, TMPRSS11B expression promoted lactate secretion concomitant with reduced levels of intracellular lactate content. Conversely, TMPRSS11B depletion in lung squamous cell cancer lines resulted in substantial accumulation of intracellular lactate. We detail a novel metabolic role of TMPRSS11B and this work identifies an oncogenic transmembrane protease that promotes tumorigenesis, thereby uncovering a new enzymatic activity that may be targeted for cancer therapy. Interrogation of lactate metabolism in vivo will ultimately guide these therapies and contribute to our growing knowledge of lactate biology.