FAU discovers possible new approach for treating colorectal cancer

The protein ZEB1 and the role its plays in connective tissue in colorectal cancer

It is not only tumor cells but also certain cells in connective tissue, especially those known as fibroblasts, that have a decisive role to play when cancer progresses and metastasizes. A team of researchers from Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) led by PD Dr. Marc Stemmler have discovered in collaboration with a working group from the University of Frankfurt led by PD Dr. Henner Farin that colorectal tumors respond better than previously to immunotherapy in animal models if a protein associated with gene regulation, ZEB1, is switched off in cancer-associated fibroblasts. In the long term, this fundamental research may improve the treatment of colorectal cancer. The results were published in “EMBO Reports”.

Colorectal cancer is the third most common type of cancer with the second highest fatality rate in the world. Nowadays, treatment has improved for colorectal cancer in the early stages, but relapses still occur, often leading to the formation of metastases. The prognosis is worse in certain sub-types of tumors that have specific characteristics. This includes tumors that have a high proportion of connective tissue cells. Cancer-associated fibroblasts are crucial players in driving the progression of the disease, therapy resistance and metastasis. The CAFs also form various subtypes.

ZEB1: An important regulating protein for the formation of metastases

The FAU researchers led by Marc Stemmler discovered that the protein ZEB1 controls the formation of subtypes and therefore the specialization of the CAFs. The fibroblast diversity regulated by ZEB1 is involved in causing tumor cells to break away from the tumor and metastasize in other organs. If ZEB1 is missing in fibroblasts, fibroblasts lose their shielding function and immune cells can penetrate the tumor more easily, preventing the progression of the disease and preventing it from spreading to other organs.
The researchers used mouse models to investigate the role of ZEB1 in fibroblasts. They discovered that switching off ZEB1 reduced the number of cancer cells migrating into the liver. At the same time, the variety of fibroblasts was reduced. In addition, inflammatory processes in the tumor microenvironment increased, with the result that tumors responded better to immunotherapy. Inflammatory processes generally encourage the activity of immune cells, or attract them.

Further research necessary

Various challenges must be tackled before the activity of ZEB1 in CAFs can be influenced in people with colorectal cancer and immunotherapies used more successfully to treat colorectal cancer. For example, first of all, medicines known as PROTACs would need to be developed to inhibit or break down the protein ZEB1 without disrupting the physiological function of ZEB1 and causing unwanted side effects. Before this method can be used in a clinical setting, we require a better understanding of CAFs and how they influence the immune environment of the tumor in patients.

DOI: https://doi.org/10.1038/s44319-024-00186-7

Further information

PD Dr. Marc Stemmler
Department of Experimental Medicine 1
Nikolaus-Fiebiger Center for Molecular Medicine
Phone: + 49 9131 85 29101
marc.stemmler@fau.de