Tiny Tumor Innovations: Crafting Miniature Growths from Circulating Cancer Cells

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Cancer cells present in the bloodstream are the “germ cells” of breast cancer metastases. They are quite uncommon and could not be cultivated in the culture dish until now, which complicated investigations into therapy resistance. A group from the German Cancer Research Center (DKFZ), the Heidelberg Stem Cell Institute HI-STEM* and the NCT Heidelberg** has now achieved, for the first time, the cultivation of stable tumor organoids directly from blood samples of breast cancer patients. Utilizing these mini-tumors, the researchers managed to decode a molecular signaling pathway that ensures the survival and resistance of the cancer cells to treatment. Armed with this knowledge, the team devised a strategy to specifically eradicate these tumor cells in laboratory experiments.

Metastases are the perilous branches of tumors that disseminate to crucial organs like the liver, lungs, or brain and are typically hard to treat. Although the outlook for breast cancer patients has significantly improved in recent decades, metastatic breast cancer continues to be a significant challenge, as the metastases often only respond temporarily to therapy.

Breast cancer metastases commence with cancer cells that disengage from the original tumor and travel to other organs via the bloodstream. These circulating tumor cells (CTCs) are incredibly rare and conceal themselves among the billions of blood cells. Andreas Trumpp, Head of a research division at the DKFZ and Director of HI-STEM, had previously demonstrated that only a handful of circulating tumor cells can form a new metastasis in another organ. These mostly therapy-resistant “germ cells” of metastases are very infrequent, challenging to isolate, and could not be multiplied in the laboratory until now. “This complicates the development of targeted new therapies that directly attack the metastasis-initiating cells. However, if we comprehend how these cells endure the initial treatment and what fuels their resistance, we could address the formation of breast cancer metastases at the source and potentially prevent them someday,” elucidates the primary author of the paper, Roberto Würth from Trumpp’s lab.

Andreas Trumpp’s team has succeeded for the first time in cultivating CTCs from blood samples of breast cancer patients and developing them as stable tumor organoids in the culture dish. Until now, this always necessitated a roundabout way, namely the intricate and time-consuming propagation of CTCs in immunodeficient mice. To understand how tumor cells develop resistance to therapies, researchers require tumor material from various time points throughout the disease’s progression. In contrast to surgical tissue removal (biopsies), blood samples are straightforward and can be collected multiple times.

The three-dimensional and patient-specific mini-tumors can be grown from blood samples multiple times during the course of the disease and are particularly suitable for investigating the molecular mechanisms that allow tumors to survive despite treatment. Moreover, preclinical tests on the effectiveness of already existing cancer medications can be conducted quickly and extensively on organoids in the culture dish.

In the clinical registry trial CATCH (ClinicalTrials.gov ID: NCT05652569) at the NCT Heidelberg, the genetic variety of patients’ breast cancer cells is being analyzed. Thanks to the successful cultivation of the organoids, Trumpp’s interdisciplinary research team, in close cooperation with the experts of the CATCH trial, was able to identify a crucial signaling pathway that ensures the growth and survival of breast cancer CTCs in the bloodstream. The protein NRG1 (neuregulin 1) functions as a vital “fuel.” It binds to the HER3 receptor on the cancer cells and, in conjunction with the HER2 receptor, activates signaling pathways that promote the cells’ growth and survival. Interestingly, even when this fuel is depleted or the receptors are inhibited by medications, the cells discover new methods. An alternative signaling pathway, managed by FGFR1 (fibroblast growth factor receptor 1), intervenes and guarantees growth and survival.

“Through such ‘bypasses,’ tumors respond to external stimuli, for instance, targeted therapies aimed at HER2. This is a vital mechanism in the emergence of therapy resistance,” explains Roberto Würth. However, there are options available: the researchers utilized organoids to demonstrate that a combined blockade of both signaling pathways (NRG1-HER2/3 and FGFR) can effectively impede the proliferation of tumor cells and induce cell death.

Andreas Trumpp summarizes: “The ability to cultivate CTCs from the blood of breast cancer patients as tumor organoids in the laboratory at various time points is a significant breakthrough. This considerably facilitates the investigation of how tumor cells develop resistance to therapies. Based on this, we can formulate new treatments that may also specifically eliminate resistant tumor cells. Another potential strategy is to modify existing therapies to reduce or even prevent the onset of resistance and metastases right from the outset. As the organoids are specific to each patient, this approach is suitable for identifying or formulating customized therapies that are optimally adapted to the respective conditions.” Before this method can be applied to treat breast cancer patients, it must first undergo clinical trials.

Reference: Würth R, Donato E, Michel LL, et al. Circulating tumor cell plasticity determines breast cancer therapy resistance via neuregulin 1–HER3 signaling. Nat Cancer. 2025:1-19. doi: 10.1038/s43018-024-00882-2

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