Tumor cells circulating in the blood are the “germ cells” of breast cancer metastases, which are rare and difficult to study. However, a team of researchers from the German Cancer Research Center (DKFZ), the Heidelberg Stem Cell Institute HI-STEM, and the NCT Heidelberg have successfully cultivated stable tumor organoids directly from blood samples of breast cancer patients, allowing them to decipher a molecular signaling pathway that promotes cancer cell survival and resistance to therapy. This breakthrough has potential implications for developing targeted therapies to eliminate these therapy-resistant tumor cells.
Metastatic breast cancer remains a major challenge despite advancements in treatment, with metastases often showing temporary responses to therapy. Breast cancer metastases are initiated by circulating cancer cells that detach from the primary tumor and migrate through the bloodstream to other organs. These circulating tumor cells (CTCs) are rare and difficult to isolate, making it challenging to develop therapies targeting them. By understanding how these cells survive initial therapy and drive resistance, researchers hope to prevent the formation of breast cancer metastases in the future.
Previous studies have shown that only a few circulating tumor cells are capable of forming new metastases, making them vital targets for therapy development. Andreas Trumpp’s team successfully multiplied CTCs from blood samples of breast cancer patients and grew them as stable tumor organoids in the culture dish. This allowed for the study of molecular mechanisms and testing of cancer drugs on patient-specific mini-tumors, providing valuable insights into therapy resistance and potential treatment options.
The ability to cultivate three-dimensional mini-tumors from blood samples multiple times during the course of the disease offers a unique opportunity to investigate the mechanisms that enable tumors to survive therapy. Preclinical tests on the efficacy of cancer drugs can be quickly and efficiently conducted on organoids in the culture dish. The genetic diversity of patients’ breast cancer cells is analyzed in clinical trials like CATCH at the NCT Heidelberg, where a key signaling pathway involving the protein NRG1 and HER receptors was identified to promote tumor cell growth and survival.
The research team also discovered that cancer cells can develop alternative signaling pathways, such as the FGFR1 pathway, to ensure growth and survival in response to therapies targeting the HER receptors. By combining blockade of both the NRG1-HER2/3 and FGFR signaling pathways, researchers were able to effectively halt tumor cell proliferation and induce cell death in organoids. This finding suggests new strategies for overcoming therapy resistance and preventing metastases in breast cancer patients by targeting multiple pathways simultaneously to disrupt tumor cell survival mechanisms.
The cultivation of CTCs as tumor organoids in the laboratory represents a significant breakthrough in understanding therapy resistance and developing targeted treatments for breast cancer patients. This personalized approach allows for the identification and development of customized therapies tailored to individual diseases, with the potential to reduce the development of resistance and prevent metastases. Before clinical implementation, the method will need to be validated in clinical trials to ensure its efficacy and safety for breast cancer patients.