Interview Questions for Nicola Aceto
Introduction:
Nicola Aceto, a renowned researcher from ETH Zurich, has made significant contributions to the understanding of circulating tumor cells (CTCs) and their role in cancer metastasis. His work, particularly the role of CTC clusters in metastasis and the discovery of circadian rhythms affecting CTC levels, has opened new avenues for cancer diagnosis and treatment.
Questions:
- Your research has significantly advanced the understanding of circulating tumor cell (CTC) clusters in the bloodstream. Can you elaborate on the mechanisms that promote the formation of these clusters and how they differ biologically from individual CTCs in terms of metastatic potential?
Clusters of CTCs, also referred to as tumor microemboli, have been observed for several decades. Early autopsy studies of patients with cancer showed their presence within the circulatory system, yet, their biological features, relevance for disease spread and vulnerabilities have been unclear. In recent years, our laboratory has contributed to defining CTC clusters as highly efficient metastatic units, capable to survive in the bloodstream and initiate metastases at distant sites. CTC clusters originate from regions of the tumor that are generally high in cell-cell junctions and hypoxic markers. Upon intravasation, CTC clusters display higher proliferative ability compared to individual CTCs, as well as activation of stem-like features that promote their metastatic behavior. Further, the multicellular nature of CTC clusters favors their physical entrapment within distant capillary networks, providing an ideal docking strategy to engage with the metastatic site. Once there, clusters take advantage of their proliferative status and stem-like features, which contribute to maximize their chances to survive and give rise to a proliferative metastatic lesion.
- One of your notable contributions includes studying the impact of the circadian rhythm on breast cancer metastasis. Could you discuss the molecular pathways through which circadian rhythm influences cancer cell dissemination and the potential implications this has for timing chemotherapy to maximize its efficacy?
Our discovery of circadian rhythms affecting the spread of breast cancer was rather unexpected. We accidentally observed that mice seemed to produce a different number of CTCs depending on blood sampling time. When looking closely at these phenomena, we could determine that in breast cancer patients and mouse models, highest CTC production occurs during sleep. While sleep is of course associated with a myriad of molecular changes that affect practically every cell in the body, we could determine that certain sleep-associated hormones could influence cancer cells behavior. In particular, melatonin was a key one. Stimulation with melatonin rapidly increases CTC production, possibly through direct binding to its receptor at the level of cancer cells. Further to CTC production, we found that the accomplishment of metastasis in breast cancer is also more likely to occur during sleep. These results may boost efforts to time treatments to when they might be most efficacious – a concept known as chronotherapy.
- Given your work on the vulnerabilities of CTCs, what are the most promising therapeutic targets you have identified, and how could these targets be exploited to develop novel anti-metastatic therapies that are both effective and minimally invasive?
This is our greatest goal for the years to come, i.e. to translate our lab findings into treatments for patients at risk of developing metastases. In recent years we have found several strategies that could be developed into anti-metastasis treatments. Among these, the most advanced one is targeting the NaK ATPase, an enzyme that normally regulates osmotic equilibrium and membrane potential in muscle cells, but that in cancer cells appears to be essential for cell-cell adhesion. Our preclinical studies in animal models using NaK ATPase inhibitors have already shown that targeting this enzyme leads to metastasis suppression. We are now proceeding in a stepwise manner to bring this approach to the clinic in the shortest possible time.
- Could you share any ongoing clinical trials or translational applications stemming from your research on CTC clusters or circadian rhythms? How close are we to seeing these discoveries implemented in clinical settings?
We have recently conducted a clinical proof-of-concept study in patients with breast cancer treated with Digoxin, a well-known NaK ATPase inhibitor, used in the past for the treatment of patients with cardiac arrythmia. Goal of this study was to assess whether the inhibition of the NaK ATPase could result in the dissolution of CTC clusters, i.e. with the purpose to confirm our mechanism of action. The study was well received by the scientific community, and even highlighted in 2023 by Nature Medicine as one of the top studies that may shape medicine. The trial is now concluded with a positive outcome, suggesting that inhibition of the NaK ATPase could potentially be used as a strategy to curb the spread of cancer. We are now working tirelessly on the development of new, even more efficient and safer NaK ATPase inhibitors that will hopefully be tested in prospective interventional studies in the next years, this time aimed at prolonging survival in treated patients.
