Shedding Light on the Mechanisms of Multiple Myeloma

Immunology researcher David R. Fooksman, PhD, is interested in the biology of plasma cells, the white blood cells (leukocytes) that produce antibodies to ward off infection. Specifically, Dr. Fooksman, an associate professor of pathology and of microbiology & immunology at Albert Einstein College of Medicine, studies the physiology of normal and malignant plasma cells: how they develop, migrate, survive and function in vivo, and in particular in the bone marrow. The bone marrow is a critical microenvironment that supports and constrains these cells, Dr. Fooksman explains. By understanding plasma cell interactions with their microenvironment, he and his laboratory team aim to develop both more-effective treatments for cancer and more-effective vaccines.

David R. Fooksman

David Fooksman, Ph.D.

To investigate these questions, Dr. Fooksman and co-workers employ cellular immunology techniques, sophisticated mouse models, and custom two-photon intravital imaging tools (high-powered microscopes) that allow them to visualize and manipulate cells in situ using live mice. “The two-photon microscope gives a birds-eye view without having to damage or expose cells to the environment,” says Dr. Fooksman. “What we see is the real biology of an immune response: how the cells are behaving, what they are interacting with, and how we can alter their behavior.”

A Promising Study

Multiple myeloma is an incurable blood cancer that develops in the bone marrow. Dr. Fooksman and colleagues recently published a new study in Leukemia entitled, “Dynamic CD138 surface expression regulates switch between myeloma growth and dissemination.” In this work, the lead authors, postdoctoral fellows Drs. Ilseyar Akhmetzyanova and Mark McCarron, address the role of CD138 or syndecan-1 on myeloma growth in the bone marrow of mice.

“CD138 is one of the most highly expressed proteins on the surface of both myeloma cells and plasma cells. Immunotherapies targeting CD138 in human patients have failed – and now we may know why,” says Dr. Akhmetzyanova.

Triggering the Switch

The major finding is that CD138 surface expression is dynamic on myeloma cells and seems to control a switch between tumor growth and spreading to other bones. At early stages of the disease, CD138 is expressed at high levels and helps myeloma cells grow, proliferate and bind to survival factors such as IL-6. But as the tumor enlarges in the bone marrow, CD138 expression decreases, coinciding with the spread of myeloma to other bones.

Blocking CD138 with immunotherapy drugs triggered myeloma cells to leave the bone marrow and spread to distant sites. Dr. Fooksman could watch myeloma cells leaving the bone marrow in real time using the two-photon microscope (see video). The Fooksman team observed that the immunotherapy could kill some myeloma cells, but also caused the cells to spread throughout the body, which was ultimately more detrimental. However, combining this treatment with standard chemotherapy made the treatments ten times more effective, suggesting a potential new treatment paradigm.

Time-lapse intravital imaging in the tibia prior to and following anti-CD138 treatment. Myeloma cell clusters (green) with blood vasculature space (red) labeled with qdot655 reveal intravasation following treatment (marked with yellow arrows).

Nutrients May be the Key

The investigators also found that surface expression of CD138 is controlled by serum factors, and that the myeloma cells could cycle CD138 on and off the surface rapidly. This means that the myeloma cells can switch between growing and spreading, based on the amount of nutrients in the bone marrow. Using myeloma cells from multiple myeloma patients, the researchers found the same behavior, suggesting it may be the same situation in humans. Future studies would be needed to unravel how myeloma cells are sensing nutrients.

“As we continue to learn more about how myeloma cells grow and spread in mice,” says Dr. Fooksman, “the closer we get to finding better ways to treat this disease in human patients.”

For more information about the Fooksman laboratory’s research, please visit: