Exploring Copper’s Role in Cancer and Cell Growth

The Chang Lab at Princeton Chemistry continues its groundbreaking work on the role of metal nutrients in human biology, a quest that began with their investigation of iron in 2024 and has now shifted to copper in 2025. Their latest research, published in Proceedings of the National Academy of Sciences, delves into the intricacies of copper in human cells, particularly how it might regulate cell growth in lung cancer. The lab’s novel sensing probe is at the heart of this study, marking a significant step forward in understanding cuproplasia—a term describing the copper-dependent growth of cells—and how this knowledge could potentially lead to new treatment modalities for cancer.

Copper: An Essential Nutrient with a Fine Balance

Copper is a crucial nutrient for human health. It is essential for a range of biological processes, including the function of enzymes involved in respiration, iron metabolism, and the production of connective tissue. Despite its importance, copper imbalances—both deficiencies and excesses—have long been associated with various diseases, including cancer. The lab’s research seeks to better understand how copper influences cancer cell behavior, specifically through a process called cuproplasia, which describes copper’s role in enabling the unchecked growth of cancer cells.

Copper’s dual nature as both a necessary nutrient and a potential contributor to disease makes it a difficult element to study. Christopher Chang, the Edward and Virginia Taylor Professor of Bioorganic Chemistry at Princeton, emphasized the challenge in studying copper’s role in health and disease. “Copper is one of the most important metal nutrients for health. It’s consumed in the diet, so it’s really nature versus nurture because every cell in every organism in every kingdom of life needs it,” he said.

Yet, when copper’s balance is disturbed, particularly in the context of oxidative stress and cancer, it can fuel the growth of tumors. This highlights the need for innovative diagnostic tools to track and understand copper-dependent cell growth in cancers. The Chang Lab has addressed this need by developing a sensing probe capable of detecting copper in human cells, marking a major leap in the study of metal nutrient imbalances in cancer biology.

The Role of NRF2 in Copper-Dependent Growth

One of the most significant discoveries in this paper is the identification of a link between copper and a key transcription factor known as nuclear factor-erythroid 2-related factor 2 (NRF2). NRF2 plays a crucial role in the body’s defense against oxidative stress. Oxidative stress arises when there is an overproduction of free radicals, which can damage cellular components, leading to diseases such as cancer. In response to this stress, NRF2 activates the expression of genes that promote the production of antioxidant proteins, helping to counteract the damage.

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The research team, led by Aidan Pezacki, a graduate student in the Chang Lab, explored how this process might intersect with copper metabolism. “Heightened levels of copper in cells are known to produce oxidative stress,” Pezacki explained. “So, we would expect cancers with a high demand for copper-dependent cell growth to also have higher levels of oxidative stress. Since NRF2 is directly responsible for combating oxidative stress, we thought it might be involved in regulating copper levels, as well.”

This insight led to a deeper investigation into the interplay between copper, oxidative stress, and NRF2. The researchers found that in lung cancer, where NRF2 levels are often elevated, NRF2 may be involved in sequestering copper, making it less bioavailable to cancer cells. This copper sequestration could, in turn, lead to vulnerabilities in cancer cells that could be targeted therapeutically.

Copper Chelation as a Potential Treatment for Lung Cancer

The novel aspect of the Chang Lab’s research is the exploration of copper chelation as a therapeutic strategy for lung cancers that have a low bioavailable copper and a high demand for copper-dependent growth. Chelation refers to the process of binding metal ions to molecules, effectively “trapping” them and preventing them from participating in biological processes. This approach has the potential to disrupt the growth of cancer cells that rely on copper.

To test this hypothesis, the team utilized National Cancer Institute (NCI) tumor cell lines to investigate the effects of copper chelation on cancer cells with varying levels of NRF2. The results were promising: cancer cells with higher NRF2 levels showed significantly higher rates of cell death when treated with a copper chelator.

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“What we found was that all the cells with higher NRF2 have higher rates of cell death when we treated them with the copper chelator,” Pezacki explained. The researchers believe that NRF2 is likely sequestering copper within the cell, and when the copper is further depleted by chelation, the cancer cells are unable to compensate for the reduced copper, leading to cell death.

This finding suggests that copper chelation could be an effective therapeutic strategy for certain types of lung cancer, particularly those where cuproplasia—copper-dependent cell growth—is prevalent. However, Chang cautioned that while this is an exciting proof-of-concept study, the results are still in the early stages, and further research is needed to translate these findings into treatments for human patients. “This is a proof-of-concept study for profiling metal vulnerabilities in lung cancer,” he said. “It’s also a platform that we think could be generally applied to not only cancer but the broader process of cell growth.”

The Broader Implications of Metal Nutrient Research

The Chang Lab’s work is part of a growing field that seeks to understand the role of metal nutrients in disease, especially in cancer. While metals like iron, zinc, and copper are essential to cellular function, their imbalance—either too much or too little—can lead to disease. This research is particularly relevant in the context of cancer, where cells often require specific nutrients in altered quantities to fuel their unchecked growth. The sensing probe developed by the lab offers a new method to identify such vulnerabilities, which could be pivotal for developing personalized treatment strategies that target specific aspects of cancer metabolism.

Chang’s team has already demonstrated the potential for copper-related vulnerabilities to serve as targets for therapeutic interventions. Building on this, the lab aims to extend its research to other types of metal-dependent cell growth and explore how these insights can be leveraged to treat a range of diseases beyond cancer. The ultimate goal is to better understand how factors such as diet, environment, and lifestyle can shape our metal metabolism and impact disease development.

Looking Ahead: The Future of Metal Nutrient Research

As the research progresses, one of the key challenges will be translating these laboratory findings into clinical applications. Copper chelation, for example, will require further testing to determine its efficacy in humans and to develop safe and effective treatments. Additionally, understanding the precise role of copper in different types of cancer will be critical for determining which patients may benefit most from this approach.

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Furthermore, the sensing technology developed by the Chang Lab could have broader applications beyond cancer treatment. By providing a more detailed understanding of copper metabolism, it could lead to new insights into other diseases where metal imbalances are implicated, such as neurodegenerative diseases, cardiovascular conditions, and even autoimmune disorders.

As researchers continue to map out the complex relationships between metals, oxidative stress, and cell growth, the Chang Lab’s pioneering work is opening the door to new diagnostic and therapeutic avenues. With their innovative approach to profiling metal vulnerabilities, they are pushing the boundaries of what is possible in personalized medicine and offering hope for more effective treatments for cancer and beyond.

Conclusion

The Chang Lab’s groundbreaking research highlights copper’s pivotal role in human biology and its potential impact on cancer cell growth. By developing a novel sensing probe to detect copper and exploring how it intersects with oxidative stress and NRF2, the team has unveiled key insights into copper-dependent processes like cuproplasia. The study’s findings offer a promising therapeutic avenue—copper chelation—for specific lung cancers where copper imbalances create vulnerabilities.

Beyond cancer, this innovative approach has broad implications for understanding and addressing diseases linked to metal nutrient imbalances, such as neurodegenerative and cardiovascular conditions. While still in its early stages, this research represents a major step toward integrating molecular insights into personalized medicine. The Chang Lab’s work not only deepens our understanding of metal biology but also sets the stage for developing more targeted and effective treatments, ultimately advancing efforts to combat complex diseases influenced by diet, environment, and lifestyle.

Reference: Marco S. Messina et al, A histochemical approach to activity-based copper sensing reveals cuproplasia-dependent vulnerabilities in cancer, Proceedings of the National Academy of Sciences (2025). DOI: 10.1073/pnas.2412816122

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