Circulating tumor cells in the bloodstream are the foundational elements for metastases in breast cancer. These cells are quite rare and, until recently, could not be cultivated in laboratory dishes, presenting challenges in studying therapy resistance. A collaborative team from the German Cancer Research Center (DKFZ), the Heidelberg Stem Cell Institute (HI-STEM*), and the NCT Heidelberg** have made a significant breakthrough by successfully growing stable tumor organoids directly from blood samples taken from breast cancer patients. Utilizing these small tumor models, the researchers were able to decode a molecular signaling pathway that aids in the survival of cancer cells and their resistance to treatment. With this insight, they developed a method aimed at selectively destroying these tumor cells in experimental lab settings.
Metastases represent dangerous offshoots of tumors that spread to critical organs such as the liver, lungs, and brain, making treatment particularly challenging. Although the outlook for breast cancer patients has improved greatly in recent decades, metastatic breast cancer remains a significant hurdle, as these metastases typically respond to treatment only temporarily.
Breast cancer metastases begin when cancer cells separate from the primary tumor and travel to other organs through the bloodstream. These circulating tumor cells (CTCs) are extremely scarce, hidden among billions of other blood cells. Several years ago, Andreas Trumpp, leader of a research division at DKFZ and Director of HI-STEM, demonstrated that only a small fraction of these circulating cells can initiate a new metastasis in distant organs. These predominantly therapy-resistant “germ cells” of metastases are notably rare, difficult to isolate, and had not been propagated in a lab setting until now. “This presents challenges for the development of targeted therapies aimed directly at the cells responsible for initiating metastases. However, by understanding how these cells survive initial treatments and what mechanisms drive their resistance, we could potentially attack the root of breast cancer metastases and possibly even prevent them in the future,” explains Roberto Würth, the lead author of the study, from Trumpp’s lab.
The team led by Andreas Trumpp has achieved, for the first time, the ability to culture CTCs from blood samples of breast cancer patients and grow them into stable tumor organoids in a lab environment. Previously, this process involved complex and time-consuming steps, including the cultivation of CTCs in immune-compromised mice. To study how tumor cells develop resistance to therapies, researchers require tumor materials from different stages of the disease. Blood samples are far easier and can be taken multiple times compared to surgical biopsies.
These three-dimensional, patient-specific mini-tumors can be grown from blood samples repeatedly during the disease’s progression, making them well-suited for exploring the molecular mechanisms that allow tumors to endure treatment. They also enable rapid and large-scale preclinical testing of already available cancer drugs within the cultured organoids.
In the clinical trial CATCH at the NCT Heidelberg, researchers are analyzing the genetic variability of breast cancer cells from patients. With the successful growth of organoids, Trumpp’s interdisciplinary team, working closely with the experts from the CATCH trial, pinpointed a key signaling pathway crucial for the growth and survival of breast cancer CTCs in the bloodstream. The protein NRG1 (neuregulin 1) acts as a critical “fuel,” binding to the HER3 receptor on cancer cells and, in conjunction with the HER2 receptor, activating signaling pathways vital for the cells’ growth and survival. Notably, even if this essential “fuel” depletes or the receptors are obstructed by medications, the cancer cells adapt through alternative signaling pathways, specifically through FGFR1 (fibroblast growth factor receptor 1), which helps ensure their continued growth and survival.
“These ‘bypass’ mechanisms allow tumors to respond to external factors, like targeted therapies against HER2. This is a critical aspect of how therapy resistance develops,” Roberto Würth explains. However, there are solutions: the research team demonstrated using organoids that a combined blockade of both signaling pathways (NRG1-HER2/3 and FGFR) can effectively halt tumor cell growth and induce cell death.
Andreas Trumpp concludes: “The ability to cultivate CTCs from breast cancer patients’ blood as tumor organoids at various points in time is a transformative advancement. It significantly simplifies the investigation into how tumor cells develop resistance to therapies. Based on this knowledge, we can formulate new treatments that may specifically target and eliminate resistant tumor cells. Another strategy could involve modifying existing therapies to reduce or even prevent the onset of resistance and metastases from the outset. Since these organoids are specific to individual patients, this approach is also ideal for identifying or developing personalized treatment plans tailored to their particular conditions.” Before these methods can be applied in treating breast cancer patients, they will need to undergo clinical trials.
*The Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM) gGmbH is a public-private partnership established in 2008 between the DKFZ and the Dietmar Hopp Foundation.
** The National Center for Tumor Diseases (NCT) Heidelberg represents a long-term collaboration involving the German Cancer Research Center, the University Hospital, and the University of Heidelberg.
