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Strategies for Preventing Dormant Cancer Cells from Being Reactivated

3D view of a growing cancer colony
3D view of a growing cancer colony and a single dormant cancer cell attached to the inner lining of bone [Dr. Michelle McDonald]

Scientists say they have uncovered the unique set of genes that keeps some cancer cells dormant. The research may reveal new therapeutic targets for multiple myeloma and other cancers which spread, or metastasize, to bone such as breast and prostate cancer, according to the team whose study (“A Niche-Dependent Myeloid Transcriptome Signature Defines Dormant Myeloma Cells”) appears in Blood.

“The era of targeted therapies has seen significant improvements in depth of response, progression-free survival, and overall survival for patients with multiple myeloma. Despite these improvements in clinical outcome, patients inevitably relapse and require further treatment. Drug-resistant dormant myeloma cells that reside in specific niches within the skeleton are considered a basis of disease relapse but remain elusive and difficult to study. Here, we developed a method to sequence the transcriptome of individual dormant myeloma cells from the bones of tumor-bearing mice. Our analyses show that dormant myeloma cells express a distinct transcriptome signature enriched for immune genes and, unexpectedly, genes associated with myeloid cell differentiation. These genes were switched on by co-culture with osteoblastic cells,” the investigators wrote.

“Targeting AXL, a gene highly expressed by dormant cells, using small molecule inhibitors, released cells from dormancy and promoted their proliferation. Analysis of the expression of AXL and co-regulated genes in human cohorts showed that healthy human controls and patients with monoclonal gammopathy of uncertain significance (MGUS) expressed higher levels of the dormancy signature genes than patients with multiple myeloma. Furthermore, in patients with multiple myeloma, the expression of this myeloid transcriptome signature translated to a two-fold increase in overall survival, indicating that this dormancy signature may be a marker of disease progression. Thus, engagement of myeloma cells with the osteoblastic niche induces expression of a suite of myeloid genes that predicts disease progression and that are potential drug targets to eradicate dormant myeloma cells.”

Most will associate cancer with its fast-growing cells that spread uncontrollably. In fact, it’s often the cancer cells that are dormant and inactive that pose the greatest threat, noted the researchers. Dormant cancer cells, when they become active, are a major cause of cancers relapsing after treatment, often as metastases, which are estimated to cause 90% of all cancer deaths.

Some cancer cells can stop dividing and hide in a dormant state in niches such as the inner lining of bones. Once dormant, the immune system cannot find them to target them and conventional chemotherapy is ineffective. There is also no way of knowing how long the cells will remain dormant.

To help prevent dormant cancer cells from being reactivated, scientists at the Garvan Institute of Medical Research are investigating what makes cancer cells dormant. But they say isolating the cells to study them has been a challenge—they are rare, often less than one in hundreds of thousands of cells in the bone, and researchers have not known how to identify them.

“What makes our approach different is that we’re looking at the cancer ecosystem as a whole,” noted Tri Phan, PhD, head of the Intravital Microscopy laboratory at Garvan and co-senior author of the study. “It’s not just the cancer cell but the other cells in their microenvironment which determine their fate. We are trying to find what genes get switched on by the microenvironment and how those genes make the cancer cell dormant.”

The Garvan researchers first developed a way to track dormant multiple myeloma cells inside the bones of living mice four years ago using a new technique called intravital two-photon microscopy. They have now isolated these rare cells to analyze the dormant cells’ transcriptome.

“Having been able to identify the rare dormant cells, we were able to isolate them and work out all the genes which were active. What is exciting is that we discovered many of these genes in dormant cells are not normally switched on in these cancer cells. Now that we know the identity of these genes, we can use that information to target them,” said Weng Hua Khoo, research officer at Garvan and first author of the study.

The team analyzed the single cell transcriptomes at the Garvan-Weizmann Centre for Cellular Genomics and confirmed their findings independently with their collaborators at the Weizmann Institute of Science.

Unexpectedly, the dormant myeloma cells had a similar transcriptome signature to immune cells, but which was only switched on when the cells were located next to osteoblasts, specialized cells found in bone. “This showed us just how crucial the crosstalk between the tumor cells and the tumor microenvironment is for cancer dormancy,” said Ido Amit, PhD, principal investigator at the Weizmann Institute.

Dr Weng Hua Khoo, Associate Professor Tri Phan and Professor Peter Croucher
Weng Hua Khoo, Tri Phan, and Peter Croucher [Garvan Institute]
The researchers are now using their method to collect data on dormant cancer cells from other cancer types, with the hope of finding a common signature that would allow them to target all dormant cancer cells. “The aim now is to bring data from many cancer types together to find a unifying approach to understanding how dormant cells control cancer relapse and metastasis,” said co-senior author Peter Croucher, PhD, research director at Garvan.

The team is also working to develop potential therapies that target the unique features of dormant cells, now uncovered by this research.

“There are different approaches to targeting dormant cells. One is to keep them dormant indefinitely by creating an environment that stops them from waking up,” continued Croucher. “A second approach is to deliberately wake them up, which can then make them susceptible to being targeted with conventional chemotherapy. But the best approach would be to use this knowledge of what the genes are that keep cells in the dormant state to eradicate them while they’re dormant. This would stop the disease coming back or relapsing. This would be the Holy Grail.”