A new immunofluorescence-based copper sensor identifies copper-specific vulnerabilities in cancer

What is it about?

Copper is an essential element for sustaining all kingdoms of life, where this metal nutrient is necessary to promote cell growth and proliferation. On the other hand, diseases such as cancer have uncontrolled increases in cell growth, which are associated with the heightened energetic needs of tumors compared to healthy tissue. As a result, many cancers also have an elevated dependence on copper. This copper-dependence on cell proliferation, which is called cuproplasia, represents a promising yet underexplored new vulnerability for cancer therapy. To this end, we developed an activity-based histochemical staining platform that enables rapid and accurate profiling of copper status as a biomarker proxy for cuproplasia, where higher amounts of bioavailable copper correlate with higher fluorescence using an antibody-based staining reagent. We used this technology to compare copper levels across the National Cancer Institute’s 60 human tumor cell line panel. From these data, we identified specific cell lines with elevated copper levels, suggesting a possible dependency on cuproplasia. Interestingly, we found that cellular copper status is regulated by NRF2, a transcription factor that promotes the expression of antioxidant gene elements to combat oxidative stress. Increased activation of NRF2 causes decreased levels of copper in non-small cell lung cancer (NSCLC) cells, with NSCLCs bearing aberrant mutations that activate NRF2 being more susceptible to selective killing by chelation therapy compared to cells with normal NRF2. This study complements previous findings from our laboratory showing a similar reciprocal relationship between high NRF activation and low iron leading to susceptibility to cell killing by iron chelation, revealing that ferroplasia and cuproplasia are newly emerging metal nutrient vulnerabilities that can be leveraged for cancer therapy.

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Photo by National Cancer Institute on Unsplash

Photo by National Cancer Institute on Unsplash

Why is it important?

By identifying that certain cancers possess low copper bioavailability that correlates with high antioxidant response driven by the transcription factor NRF2, this study advances our fundamental knowledge of how metal nutrients can regulate disease. Furthermore, this work informs translational opportunities where cancers with low copper bioavailability can be selectively targeted. Specifically, copper chelation therapy offers a promising approach for designing precision medicines for NSCLCs, which account for 80-85% of lung cancers. As the NRF2 transcription factor is typically kept at very low levels in healthy tissues, chelation therapy may have reduced off-target effects on healthy tissue with ample copper levels relative to cancers with high NRF2 activation and low copper bioavailability.