Phospholipid Found to Play a Key Role in Epithelial Cell Adhesion

Researchers in Tokyo have determined that the phospholipid phosphatidylinositol bisphosphate (PIP2) plays a role in cell adhesion and metastasis prevention, creating opportunities to enhance the lipid’s activity as a potential cancer treatment.

In multicellular organisms, body cells adhere to each other to form tissues that perform various physiological functions. Epithelial cells form our skin and lining surfaces, such as the gut and other ducts, and protect our internal organs. To maintain the integrity of an organism and function properly, it is important for these cells to remain attached to each other. They do so through specific types of cellular junctions, which are characterized by proteins that also help in maintaining cellular identity. The loss of these proteins from cell surfaces causes them to lose their identity as epithelial cells, prompting their transformation into mesenchymal cells—a process known as epithelial-mesenchymal transformation (EMT)—and subsequently, progression towards cancer and fibrosis. Since the proteins that aided in cellular adhesion are now lost, these cancerous cells can separate and migrate into the bloodstream, leading to metastasis and worsening prognosis.

The role of proteins in this process is well-understood, but how lipids are involved in cell characterization and EMT has remained a mystery.

“We know lipids are an important class of biomolecules, necessary for certain cellular functions,” says Tokyo University of Science (TUS) Associate Professor Dr. Nakamura. One such lipid, a phosphatidylinositol, forms PIP2, which is crucial for the formation of signaling molecules that regulate cell proliferation, survival, and migration. “We had evidence that higher amounts of PIP2 were found in the epidermal layer of skin, so we hypothesized that this phospholipid contributed to the properties and characterization of epithelial cells.”

To confirm that PIP2 plays a critical role in the determination of epithelial identity, the team used a battery of analytical techniques, including chromatography, mass spectroscopy, immunofluorescence, retroviral expression, and real-time quantitative PCR. “We saw that epithelial cells lost their properties when PIP2 was depleted from their cell membranes. On the other hand, osteosarcoma cells (which are cancerous, non-epithelial cells) gained epithelial cell-like properties when PIP2 was produced in their plasma membranes,” says Dr. Nakamura.

The group was also able to show that PIP2 regulates epithelial properties by recruiting Par3—a protein that guides vesicles intracellularly—to the plasma membrane. Once in the plasma membrane, Par3 facilitates the formation of adherens junctions that anchor neighboring cells together. This partially prevents EMT, and hence, progression of cancer.

 “In theory, PIP2’s partial inhibition of EMT could halt cancer progression, making this phospholipid an attractive target molecule for anti-cancer treatment,” says Dr. Nakamura.

The findings  were published recently in Nature Communications.