Metastasis, the process by which tumor cells spread to other parts of the body, is often the deadliest aspect of cancer, including breast cancer. Despite significant advancements in early detection and treatment, metastatic breast cancer remains a major challenge for clinicians. Metastatic cells are able to survive initial therapies and evade immune surveillance, causing tumors to reemerge in distant organs such as the lungs, liver, or brain. For researchers, understanding the biology of these metastatic cells—the so-called circulating tumor cells (CTCs)—has been incredibly difficult due to their rarity and their complex resistance to therapies.
For the first time, however, a collaborative team from the German Cancer Research Center (DKFZ), the Heidelberg Stem Cell Institute (HI-STEM), and NCT Heidelberg has successfully cultivated stable tumor organoids directly from blood samples of breast cancer patients. This breakthrough, recently reported in Nature Cancer, represents a significant step forward in the fight against metastatic breast cancer, providing new opportunities for treatment development and personalized therapy.
In the past, tumor cells in circulation, particularly those that initiate metastasis, were incredibly challenging to study due to their scarcity. Circulating tumor cells (CTCs) break off from primary tumors and enter the bloodstream, where they travel to distant organs to establish secondary tumors. However, CTCs make up a tiny fraction of the billions of cells in the blood, meaning isolating and studying them requires sophisticated techniques. Worse yet, few CTCs are capable of starting a new tumor at a distant site, and they possess a unique ability to resist therapy. These therapy-resistant tumor cells are generally termed the “germ cells” of metastases, and their study has been long impeded by the inability to propagate them in laboratory settings.
Roberto Würth, the first author of the study, explains the challenge in simple terms: “If we understand how these cells survive the initial therapy and what drives their resistance, we could tackle the formation of breast cancer metastases at the root and perhaps one day even prevent them.” Until this recent study, there was no reliable way to examine these cells outside of complex animal models or obtain tumor material that could offer insights into metastasis at different time points during the disease. Blood samples, by comparison, could be obtained much more frequently, allowing researchers to observe and compare changes in tumor characteristics over time, a crucial factor in identifying mechanisms of therapy resistance.
The DKFZ-HI-STEM-NCT Heidelberg team’s new method of cultivating CTCs in the laboratory represents a huge leap in overcoming this barrier. Researchers were able to grow tumor organoids—miniaturized, three-dimensional models of tumors—from blood samples taken from breast cancer patients. Unlike traditional cell culture, where cells grow in two dimensions, organoids more accurately mimic the architecture and function of tumors, making them valuable tools for research. Moreover, these tumor organoids can be propagated multiple times, allowing scientists to study changes in tumor cell behavior throughout the course of treatment. This stability and continuity offer the potential for a much deeper understanding of how tumor cells respond to various therapies.
One of the critical applications of this breakthrough is that tumor organoids derived from patient blood can be used to study therapy resistance in a highly personalized manner. This allows researchers to explore specific characteristics of each patient’s cancer and gain insights into which therapies are most likely to succeed in overcoming resistance. In clinical practice, this could pave the way for more customized treatment regimens, better tailoring drug choices to the individual’s cancer rather than relying solely on general protocols. Researchers can also perform preclinical tests on the organoids, testing the efficacy of existing cancer drugs on the newly developed models before implementing them in clinical settings.
Through the CATCH (Clinical Trial of Circulating Tumor Cells in HER2+ Breast Cancer) registry trial at the NCT Heidelberg, this team was able to achieve more in-depth insights into the biology of therapy resistance. They investigated the genetic diversity of breast cancer cells over the course of a patient’s treatment, in an effort to identify potential new targets for therapy. It was through these efforts that they uncovered a vital new molecular pathway central to the survival of CTCs in breast cancer. The protein neuregulin 1 (NRG1), they found, acts as a key “fuel” for cancer cells, particularly those with the HER2 receptor. NRG1 binds to HER3 and together with HER2, activates a cascade of signaling pathways that ensure the cancer cells’ growth and survival, even in the face of external therapy. This mechanism could allow the cells to continue thriving, even when blocked from their usual growth pathways by drugs.
Moreover, the research team found that if this primary pathway is disrupted or its effect blocked by treatment, an alternative backup pathway governed by the FGFR1 receptor takes over, enabling the tumor cells to resist treatment and continue to proliferate. This “bypass” mechanism is a well-known cause of therapy resistance in cancer, as tumors evolve to survive when their standard signaling pathways are inhibited.
“The combined activity of NRG1-HER3/2 and FGFR1 offers a formidable challenge in treating breast cancer, especially when it comes to overcoming therapy resistance,” explains Würth. However, using their new approach with tumor organoids, the team demonstrated that blocking both of these critical pathways—NRG1-HER2/3 and FGFR—could significantly reduce tumor cell growth and even induce cell death. This combination of blockade effectively halted the progression of tumors in preclinical models, providing an exciting new avenue for treatment development.
Trumpp, who leads the research division at DKFZ and serves as director of HI-STEM, sees the cultivation of CTCs from blood samples as a transformative breakthrough. “This method allows us to investigate tumor resistance in a patient-specific way, something we’ve never been able to do before,” he notes. “By isolating and expanding these rare, therapy-resistant tumor cells, we can directly test the impact of various therapeutic strategies, something that is incredibly difficult with traditional tumor samples.” He envisions this development playing a crucial role in both designing personalized therapies for breast cancer patients and discovering entirely new ways of tackling metastatic cancer before it has a chance to spread and become resistant to treatment.
While these findings have broad implications for improving treatment strategies, Trumpp cautions that further testing in clinical trials is necessary before applying the approach in the treatment of breast cancer patients. Even with significant promise shown in lab-based experiments, it will take time and careful evaluation to determine how best to integrate these discoveries into real-world therapy. Researchers are also exploring how to adapt existing therapies, so therapy resistance is less likely to develop in the first place.
Furthermore, as this approach is based on individual patient blood samples, it holds the potential for greatly improving the efficiency and effectiveness of personalized medicine in breast cancer. By tailoring therapies to the unique characteristics of each patient’s disease, it could substantially reduce the risk of recurrence and progression, marking a shift away from one-size-fits-all treatments. This could lead to better outcomes for patients, fewer side effects, and ultimately, a more targeted approach to cancer care that recognizes the complexities of each person’s tumor biology.
Reference: Nature Cancer (2025). DOI: 10.1038/s43018-024-00882-2