TY - JOUR
T1 - Transmembrane Protease TMPRSS11B Promotes Lung Cancer Growth by Enhancing Lactate Export and Glycolytic Metabolism
AU - Updegraff, Barrett L.
AU - Zhou, Xiaorong
AU - Guo, Yabin
AU - Padanad, Mahesh S.
AU - Chen, Pei Hsuan
AU - Yang, Chendong
AU - Sudderth, Jessica
AU - Rodriguez-Tirado, Carla
AU - Girard, Luc
AU - Minna, John D
AU - Mishra, Prashant
AU - DeBerardinis, Ralph J
AU - O'Donnell-Mendell, Kathryn A
N1 - Funding Information:
We thank the McDermott Center Sequencing and Bioinformatics Cores for sequencing and analysis, Jose Cabrera for assistance with figures, Michael Peyton for sharing cell lines, and Joshua Mendell and members of the O’Donnell laboratory for critical reading of the manuscript. K.A.O. is a Cancer Prevention Research Institute of Texas (CPRIT) Scholar in Cancer Research and a Kimmel Scholar. The accession number for the RNA-seq data reported in this paper is GEO: GSE114850 . B.L.U. was supported by CPRIT ( RP140110 ) and an NIH award ( T32GM008203 ). K.A.O. was supported by the NCI ( R01 CA207763 and P50 CA70907 ), the Sidney Kimmel Foundation ( SKF-15-067 ), the CPRIT ( R1101 and RP150676 ), the Welch Foundation ( I-1881 ), and the LUNGevity Foundation ( 2015-03 ). R.J.D. was supported by NCI ( R35 CA220449 ) and CPRIT ( RP160089 ). J.D.M. was supported by NIH ( P50 CA70907 , Lung Cancer SPORE) and CPRIT ( RP110708 ). C.R.-T. was supported by NIH ( 5T34GM007821-38 ).
Funding Information:
We thank the McDermott Center Sequencing and Bioinformatics Cores for sequencing and analysis, Jose Cabrera for assistance with figures, Michael Peyton for sharing cell lines, and Joshua Mendell and members of the O'Donnell laboratory for critical reading of the manuscript. K.A.O. is a Cancer Prevention Research Institute of Texas (CPRIT) Scholar in Cancer Research and a Kimmel Scholar. The accession number for the RNA-seq data reported in this paper is GEO: GSE114850. B.L.U. was supported by CPRIT (RP140110) and an NIH award (T32GM008203). K.A.O. was supported by the NCI (R01 CA207763 and P50 CA70907), the Sidney Kimmel Foundation (SKF-15-067), the CPRIT (R1101 and RP150676), the Welch Foundation (I-1881), and the LUNGevity Foundation (2015-03). R.J.D. was supported by NCI (R35 CA220449) and CPRIT (RP160089). J.D.M. was supported by NIH (P50 CA70907, Lung Cancer SPORE) and CPRIT (RP110708). C.R.-T. was supported by NIH (5T34GM007821-38).
Publisher Copyright:
© 2018 The Authors
PY - 2018/11/20
Y1 - 2018/11/20
N2 - 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.
AB - 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.
KW - Basigin
KW - CRISPR-mediated genome editing
KW - MCT4
KW - TMPRSS11B
KW - glycolytic metabolism
KW - lactate export
KW - lung cancer
KW - lung squamous cell carcinoma
KW - transmembrane serine protease
KW - transposon mutagenesis
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U2 - 10.1016/j.celrep.2018.10.100
DO - 10.1016/j.celrep.2018.10.100
M3 - Article
C2 - 30463017
AN - SCOPUS:85056739840
SN - 2211-1247
VL - 25
SP - 2223-2233.e6
JO - Cell Reports
JF - Cell Reports
IS - 8
ER -