TMEM106B drives lung cancer metastasis by inducing TFEB-dependent lysosome synthesis and secretion of cathepsins

Nature Communications
Samrat T KunduD L Gibbons

Abstract

Metastatic lung cancer is the leading cause of cancer-associated mortality worldwide, therefore necessitating novel approaches to identify specific genetic drivers for lung cancer progression and metastasis. We recently performed an in vivo gain-of-function genetic screen to identify driver genes of lung cancer metastasis. In the study reported here, we identify TMEM106B as a primary robust driver of lung cancer metastasis. Ectopic expression of TMEM106B could significantly promote the synthesis of enlarged vesicular lysosomes that are laden with elevated levels of active cathepsins. In a TFEB-dependent manner, TMEM106B could modulate the expression of lysosomal genes of the coordinated lysosomal expression and regulation (CLEAR) pathway in lung cancer cells and patient samples. We also demonstrate that TMEM106B-induced lysosomes undergo calcium-dependent exocytosis, thereby releasing active lysosomal cathepsins necessary for TMEM106B-mediated cancer cell invasion and metastasis in vivo, which could be therapeutically prevented by pharmacological inhibition of cathepsins. Further, in TCGA LUAD data sets, 19% of patients show elevated expression of TMEM106B, which predicts for poor disease-free and overall-survival.

References

Apr 7, 1997·The Journal of Cell Biology·A RodríguezN W Andrews
May 2, 2001·Proceedings of the National Academy of Sciences of the United States of America·G MotyckovaD E Fisher
Jul 11, 2001·Biochemical and Biophysical Research Communications·S CorisdeoB R Troen
Mar 3, 2004·Drug News & Perspectives·Bruce R Troen
Apr 19, 2005·Cancer Research·Nicole Fehrenbacher, Marja Jäättelä
Jul 13, 2006·Annals of the New York Academy of Sciences·Bruce R Troen
Jan 25, 2007·Cell Cycle·Vasilena Gocheva, Johanna A Joyce
Jan 27, 2009·Biochimica Et Biophysica Acta·Paul R Pryor, J Paul Luzio
Jun 27, 2009·Science·Marco SardielloAndrea Ballabio
Aug 13, 2009·Nature Reviews. Molecular Cell Biology·Paul Saftig, Judith Klumperman
Oct 20, 2009·FEBS Letters·Thomas Kolter, Konrad Sandhoff
May 27, 2011·Journal of Molecular Neuroscience : MN·Julie van der Zee, Christine Van Broeckhoven
May 28, 2011·Science·Carmine SettembreAndrea Ballabio
Jul 12, 2011·Cancer Cell·Kenneth L ScottLynda Chin
Sep 6, 2011·Developmental Cell·Diego L MedinaAndrea Ballabio
Jul 11, 2012·Oncogene·T KallunkiM Jäättelä
Aug 2, 2012·The Journal of Clinical Investigation·Young-Ho AhnJonathan M Kurie
Aug 17, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Alice S Chen-PlotkinVirginia M-Y Lee
Apr 4, 2013·Science Signaling·Jianjiong GaoNikolaus Schultz
Nov 21, 2013·Acta Neuropathologica Communications·Johanna I BuschAlice S Chen-Plotkin
Dec 21, 2013·The EMBO Journal·Benjamin M SchwenkDieter Edbauer
Jan 9, 2014·CA: a Cancer Journal for Clinicians·Rebecca SiegelAhmedin Jemal
Feb 4, 2014·Acta Neuropathologica·Yuetiva Deming, Carlos Cruchaga
Apr 2, 2014·Alzheimer's Research & Therapy·Jun-Ichi SatohKunimasa Arima
Apr 26, 2014·The Journal of Clinical Investigation·Yanan YangJonathan M Kurie
Jul 30, 2014·Molecular and Cellular Neurosciences·Massimiliano StagiStephen M Strittmatter
Nov 26, 2015·Nature Reviews. Cancer·Oakley C Olson, Johanna A Joyce
Jan 26, 2016·Nature Communications·Yiu Huen TsangKenneth L Scott
Feb 28, 2016·Current Opinion in Cell Biology·Saara Hämälistö, Marja Jäättelä
Jun 3, 2016·Journal of Cell Science·Gennaro Napolitano, Andrea Ballabio
Jul 18, 2018·Nature Communications·Caitlin L GrzeskowiakKenneth L Scott

❮ Previous
Next ❯

Citations

Apr 26, 2019·Journal of Cellular Biochemistry·Ziv Radisavljevic
Oct 2, 2019·Cancers·Francesca CuomoGilda Cobellis
Jun 24, 2020·Brain : a Journal of Neurology·Tuancheng FengFenghua Hu
Jul 18, 2018·Nature Communications·Caitlin L GrzeskowiakKenneth L Scott
Dec 16, 2020·Membranes·Brunella TanciniLorena Urbanelli
Nov 28, 2020·Bioinformatics·Gabriela A MerinoGeorgina Stegmayer
Jan 26, 2021·Frontiers in Cell and Developmental Biology·Martina La SpinaJosé A Martina
Jul 25, 2021·Nature Reviews. Molecular Cell Biology·Yan G ZhaoHong Zhang
Jan 27, 2022·EMBO Reports·Jia LinJames F Burrows

❮ Previous
Next ❯

Methods Mentioned

BETA
proteomic profiling
flow cytometry
nuclear translocation
transfection
transfections
confocal microscopy

Software Mentioned

Image

Related Concepts

Related Feeds

Calcium & Bioenergetics

Bioenergetic processes, including cellular respiration and photosynthesis, concern the transformation of energy by cells. Here is the latest research on the role of calcium in bioenergetics.