Tumor cells circulating in the blood are the “germ cells” of breast cancer metastases. They are very rare and until now could not be propagated in the culture dish, which made research into resistance to therapy difficult. A team from the German Cancer Research Center (DKFZ), the Heidelberg Stem Cell Institute HI-STEM* and the NCT Heidelberg** has for the first time succeeded in cultivating stable tumor organoids directly from blood samples of cancer patients of breast. Using these mini-tumors, the researchers were able to decipher a molecular signaling pathway that ensures the survival of cancer cells and their resistance to therapy. With this knowledge, the team was able to develop a method to specifically kill these tumor cells in laboratory experiments.
Metastases are dangerous branches of tumors that spread to vital organs such as the liver, lungs or brain and are usually difficult to treat. Although the prognosis for breast cancer patients has improved significantly in recent decades, metastatic breast cancer still poses a major challenge, as metastases often only temporarily respond to treatment.
Breast cancer metastases are initiated by cancer cells that break away from the primary tumor and migrate to other organs through the bloodstream. These circulating cancer cells (CTCs) are extremely rare and hide among billions of blood cells. Andreas Trumpp, head of a research division at the DKFZ and director of HI-STEM, had already shown several years ago that only a few circulating tumor cells are capable of forming a new metastasis in another organ. These metastasis “germ cells”, mostly resistant to therapy, are very rare, difficult to isolate and until now could not multiply in the laboratory. “This makes it difficult to develop new targeted therapies that directly attack the cells that initiate metastasis. However, if we understand how these cells survive the initial therapy and what drives their resistance, we could address the formation of breast cancer metastases from the root and Maybe one day we can even prevent them,” explains the first author of the article, Roberto Würth, from the Trumpp laboratory.
Andreas Trumpp’s team managed for the first time to multiply CTCs from blood samples of breast cancer patients and cultivate them as stable tumor organoids in the culture dish. Until now, this always required a detour: the complex and prolonged spread of CTCs in immunodeficient mice. To understand how tumor cells become resistant to therapies, researchers need tumor material from different times in the course of the disease. Unlike surgical removal of tissue samples (biopsies), blood samples are simple and can be taken multiple times.
Three-dimensional, patient-specific mini-tumors can be cultured from blood samples multiple times during the course of the disease and are ideal for investigating the molecular mechanisms that allow tumors to survive despite therapy. Preclinical tests on the effectiveness of already available anti-cancer drugs can also be performed rapidly and on a large scale in the culture dish.
The CATCH clinical registry trial at NCT Heidelberg analyzes the genetic diversity of patients’ breast cancer cells. Thanks to the successful cultivation of the organoids, Trumpp’s interdisciplinary research team, in close collaboration with experts from the CATCH trial, was able to identify a key signaling pathway that ensures the growth and survival of breast cancer CTCs in the blood . The NRG1 (neuregulin 1) protein acts as a vital “fuel.” It binds to the HER3 receptor on cancer cells and, together with the HER2 receptor, activates signaling pathways that ensure cell growth and survival. What’s also interesting is that even if this fuel is depleted or the receptors are blocked by drugs, the cells find new tricks. An alternative signaling pathway, controlled by FGFR1 (fibroblast growth factor receptor 1), intervenes and ensures growth and survival.
“With the help of these ‘bypass’, tumors react to external influences, for example to therapies directed against HER2. This is a crucial mechanism in the development of resistance to therapy,” explains Roberto Würth. But there are ways out: researchers used organoids to demonstrate that a combined blockade of both signaling pathways (NRG1-HER2/3 and FGFR) can effectively stop tumor cell proliferation and induce cell death.
Andreas Trumpp summarizes: “The possibility of growing CTCs from the blood of breast cancer patients as tumor organoids in the laboratory at different times is a decisive advance. This makes it much easier to investigate how tumor cells become resistant to therapies. On this basis we can develop new treatments that can also specifically kill resistant tumor cells. Another possible approach is to adapt existing therapies in such a way that the development of resistance and metastasis is reduced or even prevented, since organoids are specific. .for each patient, this method is suitable for identifying or developing personalized therapies that are optimally tailored to the respective diseases.” Before the method can be used to treat breast cancer patients, it must first be tested in clinical trials.
*The Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM) gGmbH was founded in 2008 as a public-private collaboration between the DKFZ and the Dietmar Hopp Foundation.
**The National Center for Tumor Diseases (NCT) Heidelberg is a long-term cooperation between the German Cancer Research Center, the University Hospital and the University of Heidelberg.