The weak spot of colon cancer cells

Colon cancer stem cells have one weak spot: the enzyme Mll1. An MDC team led by Walter Birchmeier has now shown in Nature Communications that inhibition of this protein prevents the development of new tumors in the body.

Since the introduction of colonoscopies in Germany for early detection of cancer, the number of diagnoses of advanced cancer has declined every year, as it is possible to diagnose and diagnose prognostic lesions. left immediately as part of the investigation. As a result, the death rate from colon cancer has also declined – 26 percent in women and 21 percent in men. Nevertheless, it remains the fourth deadliest cancer in the Western world – just behind lung, prostate and breast cancers. This is because the slow-growing tumors are only visible in the advanced stages of the disease and are therefore often diagnosed too late. The survival rate for advanced colorectal cancer is just five percent.

Treatment options are very limited – especially since the cancer can return even after successful chemotherapy. The recurrent cancer is often more aggressive than the original tumor, which is thought to be caused by cancer stem cells. So we took a closer look at these cells. “

Johanna Grinat, Lead study author and doctoral student, transmitted symptoms in cancer development and laboratory

Molecular conversion found in cancer gas cells

The researchers, led by Professor Walter Birchmeier, identified Mll1, a protein that regulates cell genes in mice and in human colon cancer cells. In mice, the team was able to genetically form intestinal tumors. However, if the genes did not have the gene for Mll1, it was not possible to induce tumors. And this seems to be true in humans as well: Human colon cancer cell cultures that scientists lost with cancer stem cells lost some of their stem cell properties and were less aggressive when Mll1 was blocked . Together with Professor Eduard Batlle and bioinformaticians at the IRB in Barcelona, ​​the MDC group used clinical data to show that colon cancer patients with tumors in this protein have a worse prognosis than patients with tumors in which not much Mll1.

Mll1 is an enzyme that sits on the DNA and controls the expression of specific genes “epigenetically,” as the researchers say. “It specifically does this in cancer gas cells, where the Wnt signaling pathway is strongly activated,” Grinat explains. “This means that, by putting it off, we can specifically treat cancer stem cells.”

The Wnt signal pathway regulates self-renewal and cell division. If mutations that induce Wnt signal inhibition occur more actively, the affected stem cells become more stable than healthy stem cells. They then multiply uncontrollably and form tumors. While chemotherapy slows down cell division, it can also increase the selective pressure on cancer stem cells: “They resist treatment and create new tumors that, as a result of the imitation, growing faster and even more aggressively, ”says Dr. Julian Heuberger. That is why it is so important, he explains, to understand cancer stem cell management in particular. The postdoctoral researcher is also the lead author and head of the study and now works in the Department of Hepatology and Gastroenterology in the Medical Department of Charité – Universitätsmedizin Berlin. “With Mll1,” he says, “we have found a molecular version that specifically controls the autophagy and division of cancer stem cells in colon cancer.”

Optimistic and more effective

Genetically it is not possible to “knock down a gene”, as scientists did with mice, in humans. In mice, the formation of cancer stem cells can be tracked over time and gas cells are always available for testing. However, MII1 could be inhibited by a chemical drug. Small molecules have already been developed for this research, for example, the MI-2 and MM-401 protectors, which bind to essential Mll1 bases and thus make it functional. “Understanding how these molecules work will allow us to develop these Mll1 inhibitors and even more clinically effective ones,” says Birchmeier, the last author in the study.

Healthy internal stem cells do not appear to be inhibited in the process. “We were able to use another system in mice, salivary gland cancer cells, to show that Mll1 only affects cancer cells and not healthy stem cells,” says Birchmeier. This also offers hope for the treatment of other types of cancer, as animal models have shown that head and neck tumors have the same Achilles tendon. “On the basis of our mouse studies, clinical trials are currently being conducted at Düsseldorf University Hospital to evaluate the use of Mll1 inhibitors in the treatment of head and neck tumors.”

If successful, patients with colon cancer could be treated in the future with both chemotherapy and Mll1 inhibitors, i.e., chemotherapy that specifically inhibits cancer stem cells. This increases the chances of successful treatment – even with advanced colon cancer.