Targeting dormant cancer cells

An international collaboration has revealed a unique set of genes that keep cancer cells dormant—pointing the way towards a means for preventing the spread of multiple myeloma and other cancers to the bone.

Prof. Ido Amit, from the Department of Immunology at the Weizmann Institute of Science, together with Prof. Peter Croucher and Prof. Tri Phan at the Garvan Institute of Medical Research in Australia, published these findings in the journal Blood in April. This is one of a series of published studies resulting from the combined Garvan-Weizmann Centre for Cellular Genomics.

A common problem when trying to eradicate cancer from a patient’s body—whether by surgery, chemotherapy, or other means—is that some cancer cells are in a dormant state and shielded from current therapies. Dormant cells do not proliferate or metastasize, but neither can they be detected by the body’s immune system or destroyed by chemotherapy or immunotherapy. As a result, these dormant cells become cancer’s “sleeper agents”, biding their time for some covert trigger, at which point they emerge from dormancy to grow into active cancers and to spread to the blood, bone, and then other organs. Relapses due to such re-awoken dormant cell and metastases are responsible for nearly all cancer deaths. Scientists have long tried to uncover the genes responsible for establishing and terminating the dormant state, without success.

Thanks to a collaboration between the Weizmann Institute and the Garvan Institute, the solution to this mystery is at hand.

The researchers developed an innovative method to tackle the inherent challenge to isolating rare dormant cells, using unique labeling, advanced genomics, and imaging technologies. Using that method, they tracked dormant multiple myeloma cells inside the bones of living mice. They then analyzed the dormant cells’ transcriptome—a snapshot of all the genes that are actually “switched on” in the cell (that is, decoded to produce proteins), such as those that control dormancy.

Dormant cells have a very different transcriptome than active multiple myeloma cells. The researchers now have dormant cells’ “signature”, which means they may be able to target those cells more effectively. This newfound ability to not only identify rare dormant cells, but also isolate and determine which genes were activated, is a major step forward.

Location matters

In addition, the team found that dormant myeloma cells had a similar transcriptome signature to specific immune cells—but only when the myeloma cells were located next to osteoblasts, which are specialized cells found in bone. That is, the physical location—the microenvironment—of the cells influences the type or quality of their dormancy.

“This finding showed us just how crucial the crosstalk between the tumor cells and the tumor microenvironment is,” says Prof. Amit.

“The aim now is to bring together data from many cancer types to find a unifying approach to understanding how dormant cells control cancer relapse and metastasis,” says the study’s co-senior author Prof. Croucher, Research Director at Garvan.

The Weizmann and Garvan researchers are now searching for ways to target all dormant cancer cells, and are cultivating a comprehensive understanding of how dormant cells control cancer relapse and metastasis. Moreover, knowing which genes and pathways maintain dormancy may enable the researchers to develop targeted therapies that effectively eradicate cancerous cells while they are still dormant, thereby preventing cancer relapse.

This research project within the Garvan-Weizmann Centre for Cellular Genomics is supported by the Anne Helene Toakley Charitable Foundation.

Prof. Ido Amit is supported by the Sagol Institute for Longevity Research, the Kekst Family Institute for Medical Genetics, the Thompson Family Foundation Alzheimer's Research Fund, the Adelis Foundation, the Eden and Steven Romick Post-Doctoral Fellowship Fund, the Steven B. Rubenstein Research Fund for Leukemia and Other Blood Disorders, the Alan and Laraine Fischer Foundation, the Rising Tide Foundation, the BLG Trust, the Anita James Rosen Foundation, the Felix and Silvia Schnur Endowment Fund in Stem Cell Research, the Wolfson Family Charitable Trust, Carla Hunter and Andre M. Schub, Herbert and Esther Hecht, the Estate of Simon Saretzky, and the European Research Council. Prof. Amit is the recipient of the Helen and Martin Kimmel Award for Innovative Investigation. He is the incumbent of a professorial chair established by Steven and Eden Romick.