Chronic acidosis in the tumour microenvironment selects for overexpression of LAMP2 in the plasma membrane

Mehdi Damaghi (), Narges K. Tafreshi, Mark C. Lloyd, Robert Sprung, Veronica Estrella, Jonathan W. Wojtkowiak, David L. Morse, John M. Koomen, Marilyn M. Bui, Robert A Gatenby and Robert J Gillies ()
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Mehdi Damaghi: Moffitt Cancer Center and Research Institute
Narges K. Tafreshi: Moffitt Cancer Center and Research Institute
Mark C. Lloyd: Analytic Microscopy Core, Moffitt Cancer Center and Research Institute
Robert Sprung: Moffitt Cancer Center and Research Institute
Veronica Estrella: Moffitt Cancer Center and Research Institute
Jonathan W. Wojtkowiak: Moffitt Cancer Center and Research Institute
David L. Morse: Moffitt Cancer Center and Research Institute
John M. Koomen: Moffitt Cancer Center and Research Institute
Marilyn M. Bui: Analytic Microscopy Core, Moffitt Cancer Center and Research Institute
Robert A Gatenby: Moffitt Cancer Center and Research Institute
Robert J Gillies: Moffitt Cancer Center and Research Institute

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract Early cancers are avascular and hence, profoundly acidic. Pre-malignant cells must adapt to acidosis to thrive in this hostile microenvironment. Here, we investigate MCF-7 cells that are adapted to grow in acidic conditions using SILAC proteomics and we reveal a significant upregulation of lysosomal proteins. Prominent among these is LAMP2 that functions to protect lysosomal membranes from acid proteolysis. LAMP2 upregulation by acidosis is confirmed both in vitro and in vivo. Furthermore, we show that the depletion of LAMP2 is sufficient to increase acidosis-mediated toxicity. In breast cancer patient samples, there is a high correlation of LAMP2 mRNA and protein expression with progression. We also observe that LAMP2 is located at the plasma membrane in clinical samples and this redistribution is acid-induced in vitro. Our findings suggest a potential adaptive mechanism, wherein cells chronically exposed to an acidic environment translocate lysosomal proteins to their surface, thus protecting the plasmalemma from acid-induced hydrolysis.

Date: 2015
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DOI: 10.1038/ncomms9752

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