In a very important discovery, researchers from Stanford observed that the number of expressing genes (gene counts) reduces as cells mature during tissue development. They found that cells in early stages of tissue development express more number of genes compared to fully mature cells, which express lower number of genes. In a paper published in Science, they show how gene counts decrease as human embryonic stem cells differentiate (mature) into a part of the skeletal tissue. Then, they applied this phenomenon to cells taken from breast cancer patients and successfully identified the immature cells or cancer stem cells. These cancer stem cells also showed a higher gene count. Among these genes, they identified a gene called GULP1 which was only activated in the cancer stem cells (immature cells) but not the other cells. When this gene was deactivated in patient cells implanted in a mouse model, tumour volume shrank drastically1.
What are (Cancer) Stem Cells?
Stem cells are immature precursor cells to all mature cells in a tissue and therefore the body as a whole. Only the mature cells have specific functions in their tissue whereas the job of stem cells is to keep forming mature cells and more of themselves. They are active primarily during developmental stages and during injury when tissue repair demands the production of new cells2.
In cancer development, normal cells turn rogue but the underlying mechanisms still remain. Therefore rogue cancerous tissue also has stem cells that produce more cancerous cells. These stem cells are called cancer stem cells. It is believed that these cancer stem cells are resistant to chemotherapy and therefore responsible for relapse of cancer, sometimes after many years. Therefore, scientists are trying to develop tools to target cancer stem cells during cancer therapy3,4.
Targeting Cancer Stem Cells
Although some defining characteristics have been identified, finding cancer stem cells is not straightforward. This is because they are the least abundant cells in the population. It is like looking for a needle in a haystack. Moreover, these cells are somehow resistant to therapy. Why? Because we still do not know the processes that maintain these cells5.
Using ‘Gene Counts’ to Target Cancer Stem Cells
The discovery that more number of genes are expressed in cancer stem cells compared to fully differentiated cancer cells could enable us to target them1. In this study, Gulati et al., showed quite convincingly that they could target cancer stem cells. They describe development of new computational program called CytoTRACE that can query single-cell RNA data to estimate gene counts. When they applied this program to triple-negative breast cancer patient cells, they were able to find the cancer stem cells. They confirmed their results based on previously known markers for this cancer type.
Then, they screened for genes that are unique in these stem cells. They identified the gene GULP1 and found that it was important for the survival of cancer cells. When they inactivated this gene, they clearly saw that tumour cells died1. Now, they believe that this gene could be an attractive target for next-generation chemotherapy drugs.
Triple negative breast cancer was extensively studied and some information of cancer stem cells in these type of tumours was available. However, for many other cancer types, this kind of information required to target cancer stem cells is still not available. So, treatments do not work across different cancer types. In a report published on Stanford University website, one of the author of the study, Shaheen Sikandar said, “As a cancer researcher, what I find most exciting is that this tool helps us find the tumour-initiating cells that have long been known to be responsible for resistance to treatment, metastasis and relapse after treatment.”
According to the report, the authors also believe that this research has the potential to transform how researchers hunt for stem cells associated with other diseases. Although, they have shown in different model experimental systems that they were indeed able to detect and target cancer stem cells, it remains to be seen how much of this is reproducible in different cancer types.
Regenerative medicine, in which diseased or damaged tissue is repaired through the activity of stem cells, requires the ability to isolate purified populations of stem cells specific to a given tissue. To regrow bone, the heart or the eyes, for example, researchers must first find the stem cells responsible for regrowing those organs. Finding the markers that are specific to these normal stem cells has been much like the process for finding cancer stem cell markers, the researchers said in this report. They believe that CytoTRACE, the program that they used to find these stem cells could be useful in regenerative medicine as well. Sounds very promising indeed.
Gunsagar Gulati, MD-PhD student and one of the authors of the study said, “One of the main motivations behind developing CytoTRACE was to create a tool for rapid and accurate identification of stem cells in humans, But another important question we hope to answer is how the inner workings of a cell change as the cell transforms from one state to another. This research opens up a whole new avenue of research to study how global changes in gene expression and DNA structure influence a cell’s state.”
- 1.Gulati, G. S. et al. Single-cell transcriptional diversity is a hallmark of developmental potential. Science 405–411 (2020) doi:10.1126/science.aax0249.
- 2.Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 105–111 (2001) doi:10.1038/35102167.
- 3.Gupta, P. B., Chaffer, C. L. & Weinberg, R. A. Cancer stem cells: mirage or reality? Nat Med 1010–1012 (2009) doi:10.1038/nm0909-1010.
- 4.Shibata, M. & Hoque, M. O. Targeting Cancer Stem Cells: A Strategy for Effective Eradication of Cancer. Cancers 732 (2019) doi:10.3390/cancers11050732.
- 5.LaBarge, M. A. The Difficulty of Targeting Cancer Stem Cell Niches. Clinical Cancer Research 3121–3129 (2010) doi:10.1158/1078-0432.ccr-09-2933.