Copper is an enzymatic cofactor required for cellular respiration, iron homeostasis, melanogenesis, neurotransmitter biosynthesis, and connective tissue formation. Copper deficiency in humans is evidenced by Menkes disease, a lethal pediatric disorder caused by mutations in the ATP7A copper transporter. ATP7A, a ubiquitously expressed copper transporting P-type ATPase, transports copper from the cytoplasm into the Golgi complex to supply copper to secreted copper-dependent enzymes. Additionally, ATP7A functions to export copper from cells to avoid copper toxicity. Aberrant copper metabolism is characteristic of many cancers. Copper-chelating drugs such as tetrathiomolybdate or penicillamine have been shown to have anti-angiogenic and anti-neoplastic activity. Copper also appears to be rate limiting for mitogenic signaling pathways necessary for tumor growth such as RAS/RAF/MAPK signaling. The requirement for lysyl oxidase (LOX) proteins in tumor metastasis is further illustrative of copper’s role in cancer biology. Copper-dependent LOX proteins catalyze the oxidation of lysine residues within collagen and/or elastin, stabilizing crosslinks between these fibrous proteins during the formation or remodeling of the extracellular matrix. While research implicates a direct role for LOX proteins in many types of cancer, the use of copper chelators or other strategies to starve LOX enzymes of copper as a therapeutic strategy has been largely overlooked. LOX family members acquire copper in the secretory pathway via the ATP7A protein. Consistent with this requirement, LOX activity is reduced in cultured fibroblasts derived from patients with Menkes disease that lack functional ATP7A protein. As the cancer promoting properties of LOX enzymes have been shown to require catalytic activity, we hypothesize that blocking the ATP7A protein could be a powerful approach to inhibit LOX-dependent pro-tumorigenic and pro-metastatic pathways. In this study, we have found that genetic ablation of ATP7A using CRISPR/Cas9 inhibits the tumorigenic and metastatic potential of a multiple cancer cell lines in vivo. These findings could be attributed to a variety of copper functions or those of copper-dependent enzymes, such as LOX. In this study, we investigate the role of copper-dependent enzymes, such as LOX, using in vitro and in vivo methods. While others have implicated lysyl oxidase secreted by cancer cells in tumorigenesis and metastasis, the contributions of lysyl oxidase at the metastatic site have not been evaluated. Here, I describe a novel conditional mouse model that we use to explore this question.
Citation Format: Kimberly Jasmer-McDonald, Michael Petris, Vinit Shanbhag, Nikita Gudekar. Exploring the role of copper-dependent lysyl oxidase (LOX) in metastatic growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5806. doi:10.1158/1538-7445.AM2017-5806