A single patient with cancer may have many tumor cells that display different behavior, including metastasis, growth, and response to chemotherapy. Every cancer cell utilizes its genes in a distinct method to create the required molecules. This is called its “gene Expression Signature”. To connect the signatures of gene expression with cancer progression and chemotherapy resistance, a team of researchers headed by Rong Lu from USC and Akil A. In a study that was published by Nature Communications, Merchant from Cedars-Sinai has developed a brand new genetic technology.
To develop the experimental system, the initial researcher Humberto Contreras-Trujillo of USC and his colleagues combined two existing technologies. The first technology allowed the researchers to read the gene expression signatures of individual cancer cells of patients suffering from leukemia. The second method, developed by the Lu Lab, allowed the scientists to label individual leukemia cells with heritable DNA-based “barcodes,” offering a way to monitor not only the cells but also their progenitors throughout the progression of the disease.
Utilizing this system for research using this system, the team was able to analyze the signatures of gene expression in an example of leukemia cells barcoded, then transplanted the rest of the cells into mice.
Different expression signatures of genes were linked with the organs in which cancerous cells were found in mice. CMC2 is the gene that causes cancer cells to grow in the ovaries. CMC2 cells that express high levels of the gene exhibit an ability to invade blood vessels. CMC2 cells that express low levels of the gene show colonies in the bloodstream and the spleen.
Other cancer cells that have elevated expression of the genes BTK, DNAJC, and LRIF1 tended to generate progeny in discrete pockets of bone marrow. These genes were shut down by scientists and leukemia cells experienced an increase in their migration and lost the ability to stick to bone marrow cells from other.
“In our research, we have identified previously undiscovered genes that are involved with cancer progression and resistance to chemotherapy. These genes could be potential targets for future therapies,” Lu, who is a Richard N. Merkin Assistant Professor in Stem Cell Biology, Regenerative Medicine and Biomedical Engineering at USC and a Leukemia & Lymphoma Society Scholar has said.
In proving that cancerous cells with distinct gene expression signatures tend to expand in different organs and bone marrow pockets, the study also highlighted the major challenge facing cancer researchers who study non-representative sample of patient cells. A standard blood draw does not allow the collection of non-circulating leukemia cells from patients. Even more concerning, since these pockets of cancer cells aren’t uniformly distributed, standard bone marrow biopsies may not accurately identify the disease of the patient.
Similar issues occur when patient cells are transferred to laboratory mice to conduct pre-clinical research into cancer. Less than one percent of the patient cells develop and multiply in mice.
The problem is compounded when patients’ cells are harvested from a mouse, and later transplanted into a different mouse. Serial transplantation is a common method to allow small quantities of patient cells to expand into larger amounts to conduct research. However, the new Nature Communicationsstudy shows that serial transplantations also improve the survival of cancerous cells with particular expression signatures of genes.
Relapsed cells were also less likely to survive transplantation into mice than cells from patients who received treatment for their disease. In mice transplanted it was likely that the progenitors of one or two leukemia cells from the relapsed phase were the most dominant.
Our new method revealed flaws in current leukemia models used to conduct final stages of testing before potential therapeutic therapies advance to human clinical trials. The models of leukemia don’t accurately reflect the variety of cancer cells that are present in a single person or the larger population of patients affected by this disease.
Akil A. Merchant, physician-scientist, Cedars-Sinai
Researchers also gave their mice different versions of the standard leukemia treatment plan short-term intensive chemotherapy followed by a long-term maintenance treatment. There were distinct expression patterns of genes in leukemia cells, which eventually passed away after intensive treatment, or stopped growing due to maintenance therapy, or only responded to an amalgamation of both. In actual clinical practice the combination therapy has been proven to be the most effective overall method for patients.
“By using our system for testing we have learned a lot about the way that the gene expression of individual leukemia cells influence their progression and resistance to treatment,” said Lu. “The same system can provide similar insights regarding other types of cancers, and assist in identifying and defining the specific cells that trigger the disease and cause resistance.”
Contreras-Trujillo, H., et al. (2021) Deciphering intratumoral heterogeneity using integrated single-cell tracking and clonal analyses. Nature Communications. doi.org/10.1038/s41467-021-26771-1.
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