Personalized therapy is raising hopes in the fight against breast cancer. Motivated by this, Monilola Olayioye of the University of Stuttgart's Institute of Cell Biology and Immunology (IZI) is researching the inner life and behavior of cancer cells. Olayioye, Vice Rector for Early Career Researchers and Diversity, is coordinator of the emerging research field biomedical systems at the University of Stuttgart.
Professor Olayioye, is any progress being made in the treatment of breast cancer?
Prof. Dr. Monilola Olayioye (MO): Certainly. New therapies have been developed based on a better understanding of the molecular processes that cause breast cancer. These therapies include monoclonal antibodies, that are produced by a cell line and recognize target structures on the cells of certain breast tumors in a very specific manner. The presence of these target structures on the tumors is a prerequisite for therapy.
Breast cancer patients often have a good chance of surviving if their cancers are detected at an early stage. Does that apply to all breast cancer patients?
MO That depends on the specific form of breast cancer a patient is suffering from. For example, patients suffering from hormone receptor-positive breast cancer have a very good prognosis. They can be treated with an anti hormone therapy in addition to surgical intervention. Another form of breast cancer presents a lot of HER2 growth factor receptors on the cell surface, against which the blocking antibodies mentioned above can be used. So-called triple-negative breast cancer, in which no or only low numbers of hormone receptors and the HER2 growth factor receptor are present, is a particularly aggressive form.
In general terms, why do normal body cells suddenly become abnormal and begin to proliferate in an uncontrolled manner?
MO Tumors develop when genetic changes accumulate within the cell over time. These changes canaffect both oncogenes, i.e., genes that promote growth, and tumor suppressing genes. Tumor suppressors slow down cellular growth. Mutations in tumor suppressors eliminate the mechanisms that control growth, repair errors or induce cell death.
Cancer cells can break away from the primary tumor to form metastases in remote areas of the body. Why does that happen?
MO This process is also driven by genetic changes within the cancer cell. A cell's interactions with its environment, for example with cells contained in connective tissue or cells of the immune system, also have a major influence on the metastatic process. On the one hand, the tumor cells can make themselves invisible to the immune system, and on the other hand, they can also reprogram immune cells in such a way as to facilitate metastasis.
How does this interaction between cancer and immune cells work?
MO Tumor cells become particularly invasive in the presence of certain immune cells. Tumor cells release a growth factor that attracts these immune cells and together with other factors, reprograms them. The immune cells, in turn, release another growth factor, which stimulates the tumor cells thus creating a self-reinforcing cycle that facilitates metastasis. We've modeled this circuit in our lab in three-dimensional tissue cultures in which breast cancer cells are grown in conjunction with immune cells rather than in isolation. This recapitulates the situation within the body more closely than conventional two-dimensional cell cultures do. In such 3D systems, we have been able to elucidate a new molecular regulatory mechanism that reinforces the reciprocal interactions between breast cancer cells and immune cells.
What other factors cause the progression of a cancer?
MO I am very much interested in changes of the cytoskeleton, the inner structure of cells that also determines their shape. What we see is that cancer cells actively change their shape, especially during the process of metastasis. However, the cytoskeleton also influences the transmission of growth factor receptor signals, this interaction is precisely what I'm investigating in more detail with my team. As we've been able to demonstrate in several publications, not only does the loss of certain tumor suppressors, which regulate the cytoskeleton result in increased cell motility, it also enhances the activity of HER growth factor receptors. Here we're working closely with Dr. Angelika Hausser at our institute.
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Networked disciplines and interdisciplinary collaboration at the University of Stuttgart
A new project in collaboration with Prof. Albert Jeltsch of the University of Stuttgart's Institute of Biochemistry and Technical Biochemistry (IBTB) is focusing on epigenetic changes in breast cancer. What's that about?
MO Epigenetic changes are usually reversible chemical modifications in the DNA that influence which genes are turned on or off within the cell. This also creates different cell types. Epigenetic changes within cancer cells, for example, switch tumor suppressor genes off. One interesting therapeutic approach may be to reverse these epigenetic changes, thus inhibiting tumor growth.
What exactly do you want to study in this project?
MO We want to use specific fluorescent sensors developed in Prof. Jeltsch's department to visualize epigenetic changes in living breast cancer cells. This will enable us to microscopically check whether certain tumor suppressor genes have been turned off. Conversely, we will also be able to find out whether the drugs that remove epigenetic changes from the DNA reactivate these silenced tumor suppressor genes.
Getting back to the aggressive triple negative form of breast cancer, for which there are currently only a few treatment options: what targeted therapeutic approaches can you imagine for this subtype?
MO Very often, another growth factor receptor, the HER1 or EGF receptor, is found on these tumors. Simply blocking this receptor alone is not enough to prevent the breast cancer cells from growing. If one signaling pathway is blocked, this often causes other compensatory signaling pathways to be turned on. However, by blocking two different growth factor receptors in parallel, the HER1 and HER3 receptors, the growth of triple-negative breast cancer cells was inhibited both in cell culture and in animal models. Together with Prof. Roland Kontermann at our institute we were able to demonstrate this.
“Prevent the growth of breastcancer cells.”
Monilola Olayioye, Professor of Molecular Tumor Cell Biology
What other challenges are researchers who want to develop new breast cancer treatments facing?
MO Another difficulty is that even triple negative breast cancer can be divided into further subgroups. In fact, in the future we will have to obtain a kind of molecular fingerprint of each individual tumor, based on which promising tailored treatment programs can be designed. This requiresa holistic understanding of the modified signaling pathways in breast cancer at the systems level. Within the Stuttgart Research Center Systems Biology (SRCSB), we are collaborating with colleagues from other faculties to develop mathematical models of the signaling pathways in cancer cells, with the objective to predict the behavior of cancer cells and the efficiency of molecular treatments.
Do you think it will be possible to cure cancer in the future?
MO Due to the diversity of cancer types, fully curing cancer will remain a challenge in the near future. However, by improving treatments, we envisage that cancer may become a chronic disease with which cancer patients can grow old. And this is where I see great potential in targeted therapeutics.
Interview: Helmine Braitmaier
Dr. Eric Heintze
Project manager Let US start! and Staff Position of the Rector in the Office of the Rectorate, University of Stuttgart
This interview was published in the magazine “forschung leben”.