Researchers at the University of Cincinnati Cancer Center detail how the accumulation of copper helps clear cell renal cell carcinoma (ccRCC)—the most common type of kidney cancer—grow and advance in stage in a new study. The results were published in Cancer Discovery.
Copper is a necessary trace element required for body energy production and enabling our life in an oxygen-containing atmosphere. Indeed, the worse outcomes for patients with ccRCC, lead author Maria Czyzyk-Krzeska, MD, PhD, of the Cancer Center, noted, are linked to an increase in accumulation of copper. In a multidisciplinary approach, Czyzyk-Krzeska and colleagues determined the level of copper in ccRCC cells progresses from stage 1 to metastatic disease.
High concentrations of copper enable the cancer cells to produce a special enzyme that allows them to generate more energy and grow faster, the team found. Additionally, glucose helps by creating a protective molecule called glutathione. This molecule provides cancer cells with a survival advantage by clearing toxins and mitigating some of the damage caused by copper.
Simply put, copper orchestrates cancer cell adaptation at multiple levels, which results in the development of a tumor, said Czyzyk-Krzeska, professor, Department of Cancer Biology, College of Medicine, UC. “This causes a switch in a cell’s metabolic state.”To determine that ccRCC tumors have ‘hot spots’ with enriched copper-dependent energy production, the team used single-cell RNA sequencing and spatial transcriptomics. Meanwhile, these hot spots are located adjacent to other tumor cells that exhibit features of proliferation that are necessary for tumor growth.
‘Czyzyk-Krzeska said that is very important because it can help us hypothesize that those proliferative cells are sustaining themselves by the metabolically active cells.’ “We can also suggest that some of these cells become metabolically active, but also some of them potentially progress to become more proliferative.”
Still, it may now be known how copper enables ccRCC cells to thrive, but precisely what is driving copper buildup in these tumors, Czyzyk-Krzeska says, remains a mystery. Environmental exposures such as tobacco smoking, e-cigarette use, or wildfire smoke that is heavy in copper are thought to account for the copper accumulation, according to experts.
Czyzyk-Krzeska still has significant research to do but said that research has helped identify weaknesses that could be targeted with new treatments. She noted that these treatments could resemble co-therapies that work on both the metabolic and proliferative cells.
Copper in patient specimens can also be used as a biomarker to help predict how aggressive the cancer is or if it is likely to come back after initial surgery, said the researchers. Julio Landero Figueroa, PhD, of the Icahn School of Medicine at Mount Sinai also had to conduct metallomic analytical chemistry to determine copper levels in human, animal, and cell line models of OSHD, as did the Czyzyk-Krzeska lab’s molecular biology work.
Czyzyk-Krzeska said it’s a ‘typical example’ of the kind of team science that can occur when chemists, bioinformaticians, cancer biologists, and physicians cooperate.
In conclusion, potential copper-induced mechanisms promoting ccRCC progression have been reviewed in detail particularly by metallomics, metabolomics, lipidomics, and transcriptomics, using patient tumors, xenograft models, and cell line studies.
Reference: Bischoff ME, Behrouz Shamsaei, Yang J, et al. Copper drives remodeling of the metabolic state and progression of clear cell renal cell carcinoma. Cancer Discovery. Published online October 30, 2024. doi: https://doi.org/10.1158/2159-8290.cd-24-0187
