Leucine-rich repeat-containing protein 15, or LRRC15, is a protein that belongs to a large family known for roles in cell signaling and adhesion. Found on the surface of certain cells, LRRC15 is being studied for its distinct functions in the body’s response to disease. The protein’s involvement in different biological processes has made it a subject of research, opening new avenues for understanding its contribution to both health and pathology.
The Biological Function of LRRC15
LRRC15 is located on the surface of specific cell types, most notably fibroblasts. These are the cells responsible for building the structural framework of tissues, known as the extracellular matrix, which provides support and integrity to organs. In connective tissues like the placenta, skin, and lungs, LRRC15 is involved in interactions between cells and the surrounding matrix, binding to components like collagen and laminin.
The presence of LRRC15 on fibroblasts suggests a role in tissue maintenance and repair. Its functions include helping to regulate how cells attach to one another and to the extracellular matrix, which is important for wound healing and maintaining the normal architecture of tissues. While it has limited expression in healthy tissues, its levels can increase when tissues are perturbed or undergoing repair.
Role in Viral Infections
The function of LRRC15 gained public visibility during the COVID-19 pandemic. Research revealed its role in the body’s interaction with the SARS-CoV-2 virus. The protein acts as a binding partner for the virus’s spike protein, the component the virus uses to enter cells. Unlike the ACE2 receptor, which facilitates viral entry, LRRC15 does not appear to help the virus infect the cell it is on, instead functioning like a molecular trap.
LRRC15 is found on lung fibroblasts, which are not the primary cells infected by SARS-CoV-2. When the virus encounters these fibroblasts, LRRC15 can bind to the spike protein, sequestering the virus particles. This action prevents the virus from reaching and binding to ACE2 receptors on vulnerable lung epithelial cells. Studies have shown that LRRC15 expression is induced in the lungs of patients with severe COVID-19, where it lines the airways.
By capturing the virus, LRRC15 on fibroblasts may reduce the overall viral load available to cause infection. The interaction between LRRC15 and the virus also appears to trigger antiviral responses within the fibroblasts, promoting the expression of genes that help fight the infection. Some research indicates that LRRC15 can suppress collagen production, potentially mitigating the lung fibrosis seen in severe COVID-19 cases.
Involvement in Cancer Progression
In contrast to its protective role in viral infections, LRRC15 plays a harmful part in cancer. The protein is found at high levels in the tumor microenvironment, the ecosystem of cells and matrix that surrounds a tumor. It is expressed on the surface of cancer-associated fibroblasts (CAFs), a specialized type of fibroblast that supports tumor growth in various solid tumors, including those of the breast, pancreas, and lung.
Within this environment, LRRC15 contributes to creating conditions that help cancer cells thrive and evade the immune system. The presence of LRRC15 on CAFs is associated with an immunosuppressive environment, making it difficult for the body’s immune cells, such as T cells, to recognize and attack the tumor. High levels of LRRC15 often correlate with resistance to immunotherapy and a poorer prognosis for patients.
LRRC15 also facilitates cancer cell migration and invasion. It interacts with other proteins on the cell surface and in the extracellular matrix to promote signaling pathways that drive cell movement. In some cancers, LRRC15 expression on CAFs has been shown to increase the production of enzymes that break down the surrounding tissue, allowing cancer cells to spread more easily. This dual function makes LRRC15 a factor in cancer progression.
Therapeutic Targeting of LRRC15
The dual nature of LRRC15 has led scientists to explore it as a therapeutic target. For viral diseases like COVID-19, the goal is to leverage its protective qualities. Researchers are investigating the development of drugs that can mimic the action of LRRC15, acting as soluble decoys that bind to viruses and neutralize them before they can infect cells. This approach could lead to new antiviral treatments.
Conversely, in oncology, the strategy is to eliminate cells that express LRRC15. Because the protein is highly expressed on cancer-associated fibroblasts but has limited presence in healthy tissues, it presents a specific target. One approach is the development of antibody-drug conjugates (ADCs). These therapies link a cancer-killing drug to an antibody that specifically seeks out and binds to LRRC15.
One such ADC, known as ABBV-085, has been studied in preclinical models. The antibody delivers a toxic payload directly to the LRRC15-positive cells. The drug payload is cell-permeable, meaning that once released, it can also kill adjacent tumor cells that may not express LRRC15, creating a bystander effect. This strategy aims to dismantle the supportive environment of the tumor and directly attack the cancer.