Analysis of Cancer Stem Cells with MutaSeq Opens up New Research Possibilities

Scientists from the e:Med junior alliance LeukoSyStem have developed the method MutaSeq, that can distinguish cancer stem cells, mature cancer cells, and healthy stem cells based on their genetics. The method enables researchers to create highly detailed profiles of cancer cells, helping them understand every individual cell from a cancer. The result of this study opens up new possibilities in cancer research.

Most cancer cells divide fast, but can’t divide indefinitely. Cancer stem cells, on the contrary, have a high self-renewal capacity, and are capable of generating new mature cancer cells for years. In Leukemias, cancer stem cells are believed to be the source of a relapse after the patients have entered remission following treatment. The relapse constitutes a major cause of death, with only 15% of elderly acute myeloid leukaemia patients surviving the disease longer than five years. A challenge in addressing the relapse is the difficulty to isolate and study cancer stem cells. Due to their scarcity and the similarity of cancer stem cells to healthy stem cells, it is difficult to effectively pinpoint the problematic cells and develop precision treatments that target cancer stem cells while saving the others.

Researchers of the e:Med LeukoSyStem junior research alliance led by Simon Haas (group leader at HI-STEM gGmbH and German Cancer Research Center (DKFZ)) in collaboration with colleagues from Center for Genomic Regulation (CRG) and European Molecular Biology Laboratory (EMBL) have tackled this problem by developing MutaSeq. The MutaSeq method distinguishes cancer stem cells, mature cancer cells, and healthy stem cells based on their genetics and gene expression.

“MutaSeq works similar to a Corona PCR test, but is much more complex and starts with a single cell”, explains Lars Velten, Group Leader at CRG and first author of the paper. “To detect a Corona virus infection, they first measure Corona RNA levels. To determine if it’s the British variant, they then sequence the Corona RNA. What we did to determine if a cell is a stem cell, was to first measure 1,000s of RNAs at the same time, since there is no single ‘stem cell RNA’. To determine if the cell is cancerous or healthy, we then additionally sequence these RNAs and look for mutations. MutaSeq does all of this in one go, starting with just one cell. Thereby we can track if stems cells are cancerous or healthy, and determine what makes the cancer stem cells different”.

“There is a huge number of small molecule drugs out there with demonstrated clinical safety, but deciding which cancers and more specifically which patients these drugs are well suited for is a daunting task,” says Lars Steinmetz, Professor at Stanford University, Group Leader at EMBL Heidelberg. “Our method can identify drug targets that might not have been tested in the right context. These tests will need to be carried out in controlled clinical studies, but knowing what to try is an important first step.”

The method is based on single cell sequencing, an increasingly common technique that helps researchers gather and interpret genome-wide information from thousands of individual cells. Single cell sequencing provides a highly detailed molecular profile of complex tissues and cancers, opening new avenues for research.

“We have now brought together clinical researchers from Germany and Spain to apply this method in much larger clinical studies”, says Lars Velten. “Also, we are making the method much more streamlined. Our vision is to identify cancer stem cell specific drug targets in a personalized manner, making it ultimately as easy for patients and doctors as currently Corona tests”.

Original publication:

Velten, L., Story, B.A., Hernández-Malmierca, P., Raffel, S., Leonce, D.R., Milbank, J., Paulsen, M., Demir, A., Szu-Tu, C., Frömel, R., Lutz, C., Nowak, D., Jahn, J.C., Pabst, C., Boch, T., Hofmann, W.K., Müller-Tidow, C., Trumpp, A., Haas, S. & Steinmetz, L.M. (2021) Identification of leukemic and pre-leukemic stem cells by clonal tracking from single-cell transcriptomics. Nat Commun 12, 1366  https://doi.org/10.1038/s41467-021-21650-1

LeukoSyStem Junior Research Alliance

Dr. Simon Haas
BIH at Charité, Berlin
Max Delbrück Center, MDC, Berlin
Hi-STEM, Heidelberg
German Research Cancer Center, DKFZ, Heidelberg

Prof. Dr. Lars Steinmetz
European Laboratory of Molecular Biology EMBL, Heidelberg

Dr. Lars Velten
Center for Genomic Regulation, CRG, Barcelona