Cellular communication is vital for passing information to neighboring cells. One key messenger in this process is an exosome, a nanosized particle that buds off from a progenitor cell, carrying molecular cargo. Because these small, cellular vehicles carry contents from their parent cells, exosomes can serve as snapshots for a given population of cells, including tumors.
“If you can sample a vesicle, or any entity, from blood, it gives you a huge advantage, being a low or minimally invasive strategy to monitor cancer or detect cancer,” said David Greening, a biologist who studies extracellular vesicles like exosomes at La Trobe University.
One strategy to improve the use of exosomes as cancer biomarkers is to identify surface proteins on these vesicles that reflect their originating tumor.1 L-type amino acid transporter 1 (LAT1), a surface protein that shuttles large amino acids into the cell, is predominantly associated with cancerous cells and correlates with tumor severity.2,3 These characteristics made the protein an attractive target for therapeutic intervention, with one LAT1 inhibitor currently undergoing clinical trials.4
Ryuichi Ohgaki and his team study LAT1 in the context of cancer. Now, they are interested in its potential as a druggable biomarker.
Ryuichi Ohgaki
In a study published in Scientific Reports, researchers demonstrated the potential of LAT1 on exosomes from pancreatic and other cancer cell lines as a biomarker. 5 “[Now] we can detect and treat cancer using the same target,” said Ryuichi Ohgaki, a pharmacologist at Osaka University and study coauthor.
Ohgaki and his team studied the role of LAT1 in driving cancer progression for years. Inspired by previous work that measured cancer-associated proteins on exosomes, the group set out to investigate the correlation between LAT1 expression on exosomes and their originating cancer cells.
To explore this relationship, the team used ultracentrifugation to isolate these particles from human pancreatic, cervical, and bile duct tumor cell lines. In most of the tested cell lines, LAT1 expression on exosomes correlated with LAT1 expression on cell membranes.
To study exosomes in vivo, the team introduced pancreatic cancer cells into the peritoneal cavity of mice. One month later, they used immunohistochemistry to measure LAT1 expression in tumor tissue and adjacent nontumor cells, finding the protein exclusively in the tumor tissue. When they isolated exosomes from the peritoneal cavities of tumor-bearing and control mice, they detected greater LAT1 expression on the vesicles from the mice with tumors.
According to Ohgaki, the advantage of pursuing LAT1 as a biomarker is its dual potential as both a diagnostic and a therapeutic target. Toward this goal, he and his team are exploring ways to optimize the use of exosomal LAT1. One approach involves developing an antibody that can detect the surface-exposed portion of LAT1. Although LAT1 is a surface marker, the team used an antibody that recognizes an intra-exosomal region of the protein, requiring them to lyse the exosomes to confirm LAT1 expression.
LAT1 on cancer-cell derived exosomes could serve as a diagnostic marker for cancer.
Ryuichi Ohgaki
“If we can make such an antibody, we can directly detect LAT1 on liquid biopsy, like blood or plasma,” Ohgaki said. Greening, who wasn’t involved in the study, echoed the importance of targeting the surface portion of LAT1 with an antibody to improve its potential as a biomarker.
Additionally, establishing more sensitive means to identify LAT1 on exosomes could also improve its detection at lower volumes of exosomes, like in the blood and during the early stages of cancer progression. Since the in vitro studies compared exosomes from cancer cells, Greening said that he is also interested in seeing how well LAT1 discriminates between exosomes from healthy and diseased cells.
“This is quite preliminary in discovery, in terms of can we identify a marker in an extracellular vesicle that may indicate the onset of pancreatic cancer,” said Greening. However, because there are limited diagnostic and treatment options for pancreatic cancer, he added that identifying early markers of the disease is needed. “There’s huge potential here to find something that can help many patients.”
