Life science
Medicine / Healthcare, Drug discovery

Molecular mechanism of adaptation of cancer cells to acidicenvironments
Department of Cellular Regulation, Research Institute for Microbial Diseases
Professor Hiroaki Miki

Researchmap https://researchmap.jp/read0056900

Assistant Professor Yosuke Funato

Researchmap https://researchmap.jp/read0156495

Life science

Abstract
Cancer cells have a unique energy metabolism that consumes
large amounts of glucose to produce lactic acid, which acidifies themicroenvironment surrounding cancer cells. However, it has long
been unclear how cancer cells survive and proliferate in an acidic
environment that is harmful to normal cells. We found that PRL, amolecule that is specifically expressed in malignant cancer tissues
such as colorectal cancer metastases, enables cells to selectively
proliferate in acidic environments. In cells expressing high levels ofPRL, lysosomal exocytosis, in which lysosomes fuse with the cellmembrane, is activated, and H+ stored in the lumen of lysosomes
is expelled, maintaining the intracellular pH at an appropriate leveleven in an acidic environment. Furthermore, cancer cells that losttheir ability to proliferate selectively in an acidic environment byinhibiting lysosomal exocytosis were also strongly inhibited fromforming tumors in vivo, indicating the importance of this adaptation
phenomenon to acidic environments in tumorigenesis.

▍ Significance of the research and Future perspective
Tissue acidification is well known as a characteristic of the microenvironment surrounding cancer cells, along with hypoxia, andthus, clarifying the molecular basis of the adaptation phenomenon
is an important achievement of this study. The clarification of themolecular mechanism that is the key to the growth of cancer cellsin vivo may lead to the development of new diagnostic and therapeutic agents that target this mechanism.

▍ Background & Results
Cancer cells have a unique energy metabolism that consumes
large amounts of glucose to produce lactic acid, which acidifies the
microenvironment surrounding cancer cells. However, it has long
been unclear how cancer cells survive and proliferate in an acidic
environment that is harmful to normal cells. We have been analyzing the function of PRL, a molecule that is specifically expressed inmalignant cancer tissues such as metastases of colorectal cancer,and have reported the Mg2+ transporter CNNM as a direct target ofPRL. Here, we found that PRL-expressing cells can hardly proliferate at physiological pH 7.4, but proliferate selectively in acidic environments such as pH 6.5, which is typically observed in cancer
tissues. We performed various analyses, including comprehensive
gene knockout screening using CRISPR/Cas9, to elucidate themolecular mechanism underlying this phenomenon, and foundthat lysosomal exocytosis, in which lysosomes fuse with the cellmembrane, is activated. The activation of lysosomal exocytosis
maintains the intracellular pH at an appropriate level even in anacidic environment by secreting a large amount of H+ stored in thelumen of the lysosome. Since it was known that the Ca2+ channel
TRPML, which is localized at the lysosomal membrane, is essential
for this lysosomal exocytosis to occur, we knocked out this molecule and found that the cells were unable to actively proliferate inacidic environments when PRL was overexpressed. Furthermore,even in cancer cells whose tumorigenicity in vivo was increasedby high PRL expression, TRPML knockout inhibited their growthin acidic environments and greatly reduced their tumorigenicity.
These results indicate that the activation of lysosomal exocytosis
plays an important role in the adaptation of cancer cells to acidic
environments and tumorigenesis, and reveal the response mechanism of cells to acidic environments, a prominent characteristic ofthe cancer microenvironment.

P a t e n t
Tr e a t i s e

Funato, Yosuke; Yoshida, Atsushi; Hirata, Yusuke et al. The oncogenic PRL protein causes acid addiction of cells by stimulating lysosomal exocytosis.
Developmental Cell. 2020; 55: 387-397. e8. doi: 10.1016/j.devcel.2020.08.009. Epub 2020 Sep 11

URLK e y w o r d cancer, acidic environments, PRL, lysosome