Insight into link between lysosomal activities and focal adhesions and implications for cancer research

The fight against cancer often begins with uncovering hidden players, and this study reveals one such key player: an unexpected class of abbreviated N-glycans. These molecules, upregulated in cancer cells, are excreted through a surprising mechanism—lysosomal exocytosis. Even more fascinating is the intricate relationship between lysosomal exocytosis and focal adhesions, structures critical for cell anchoring and communication. By decoding how focal adhesions regulate lysosomal exocytosis, researchers are opening new doors to understanding cancer cell adhesion and migration and exploring innovative therapies targeting these molecular interactions.

Researchers published their results in the Journal of Cell Biology on January 3, 2025.

Lysosomes are organelles found within nearly all eukaryotic cells and are responsible for breaking down larger molecules such as proteins, fats and carbs. Lysosomal exocytosis occurs when the lysosomes fuse with the plasma membrane of a cell to expose and release their contents outside of the cell. Essentially, lysosomes and lysosomal exocytosis act primarily as a means of keeping the cell free of “trash” that can get in the way of cells, and thereby the organism as a whole, working properly.

Other functions of lysosomal exocytosis include repairing injuries to the plasma membrane, cell-to-cell communication and, unfortunately, can aid the progression of tumors. Many cancer cells have increased levels of paucimannose glycans, which are not commonly seen in vertebrate cells outside of the context of cancer. The humble lysosome, which carries out so many essential functions, appears to live a double life as a potential traitorous agent.

“The study highlights the close interaction between lysosomal exocytosis and focal adhesions, underscoring their critical role in cancer cell adhesion, migration, and tumor progression,” said Morihisa Fujita, author and researcher of the study.

Paucimannosidic proteins are revealed to be produced by lysosomal glycosidases (enzymes within a lysosome that break down glycoproteins such as paucimannose glycans) and are often involved in cell proliferation and survival, key aspects to cancer cell behavior. These proteins are excreted outside of the cell, and as discovered through this study, the area of lysosomal exocytosis appears to be strongly correlated with the proximity to focal adhesions.

Focal adhesions (FAs) are structures that connect cells to the extracellular matrix (ECM) or the cell’s external surroundings composed of collagen, elastin and other complexes to support the overall structure and function of a cell. Integral to this study is MYO18B, a gene most often found in human cardiac or skeletal muscle tissue and is responsible for regulating lysosomal exocytosis through the promotion of focal adhesion maturation.

This gene was pinpointed as a regulator of the process and integral to the promotion of assembling stress fibers needed for FA maturation. The targeted nature of lysosomal exocytosis near FAs could have arisen from the need for lysosomal enzymes to be released to perform functions relating to cell-to-ECM interactions.

Further research will be necessary to form a more accurate picture of the relevance of paucimannosidic proteins excreted through lysosomal exocytosis in cancer biology, particularly as to how cancerous cells might migrate through lysosomal activities.

However, researchers are interested in the possibility of the information garnered through this study to spur the development of new cancer therapies that specifically target paucinmannose glycans and lysosomal exocytosis mechanisms.

Wei-Wei Ren and Morihisa Fujita of the Institute for Glyco-core Research at Gifu University and  the Key Laboratory of Carbohydrate Chemistry and Biotechnology at Jiangnan University, Ganglong Yang of the Key Laboratory of Carbohydrate Chemistry and Biotechnology at Jiangnan University and the State Key Laboratory of Biochemical Engineering at the Chinese Academy of Sciences, Rebeca Kawahara and Morten Thaysen-Anderson of the Institute for Glyco-core Research at Nagoya University, Kenichi G. N. Suzuki of the Institute for Glyco-core Research at Gifu University and the Division of Advanced Bioimaging at the National Cancer Center Research Institute, and Priya Dipta and Morten Thaysen-Anderson of the School of Natural Sciences at Macquarie University all contributed to this research.

The Japan Society for the Promotion of Science, the KAKENHI Grant, the National Natural Science Foundation of China, the J-GlycoNet cooperative network, the JSPS Core-to-Core Program, the Human Glycome Atlas Project (HGA) from the Ministry of Education, Culture, Sports, Science and Technology and Takeda Science Foundation supported this research.