Abstract
The vast majority of cancer-related deaths are due to metastatic disease, whereby primary tumor cells disseminate and colonize distal sites within the body. Triple negative breast cancer typically displays aberrant Wnt signaling, lacks effective targeted therapies, and compared with other breast cancer subtypes, is more likely to recur and metastasize. We developed a Wnt-driven lung metastasis model of triple negative breast cancer (metM-Wntlung) through serial passaging of our previously described, nonmetastatic, claudin-low M-Wnt cell line. metM-Wntlung cells displayed characteristics of epithelial-to-mesenchymal transition (e.g., increased invasiveness) with some re-epithealization (e.g., increased adhesion, tight colony formation, increased E-cadherin expression, and decreased Vimentin and Fibronectin expression). When orthotopically transplanted into syngeneic mice, metM-Wntlung cells readily formed tumors and metastasized in vivo, and tumor growth and metastasis were enhanced in obese mice compared with non-obese mice. Gene expression analysis revealed several genes and pathways altered in metM-Wntlung cells compared with M-Wnt cells, including multiple genes associated with epithelial-to-mesenchymal transition, energy metabolism and inflammation. Moreover, obesity caused significant transcriptomic changes, especially in metabolic pathways. Metabolic flux analyses showed greater metabolic plasticity, with heightened mitochondrial and glycolytic energetics in metM-Wntlung cells relative to M-Wnt cells. Similar metabolic profiles were found in a second triple negative breast cancer progression series, M6 and M6C cells. These findings suggest that metabolic reprogramming is a feature of metastatic potential in triple negative breast cancer. Thus, targeting metastases-associated metabolic perturbations may represent a novel strategy for reducing the burden of metastatic triple negative breast cancer, particularly in obese women.
Highlights
Metastasis is the dissemination and formation of secondary tumors at distal sites that causes most of the morbidity and mortality associated with triple-negative breast cancer (TNBC) and most other cancer types.[1, 2] Key characteristics of metastatic cells include the ability to migrate, invade surrounding tissue, to survive in the periphery, and to attach to and colonize distal sites in the body
In vitro characterization of metM-Wntlung cells The metM-Wntlung cell line was generated by serial transplantation of green fluorescence protein (GFP)-luciferase labeled nonmetastatic M-Wnt cell line (Fig. 1a) in five generations of severe-combined immunodeficient (SCID) mice (n = 3)
Mice were monitored for luciferase-positive lung metastases (Fig. 1b), and once detected, tumors were harvested, cells were sorted by flow cytometry according to GFP expression, and the metM-Wntlung cell line was established
Summary
Metastasis is the dissemination and formation of secondary tumors at distal sites that causes most of the morbidity and mortality associated with triple-negative breast cancer (TNBC) and most other cancer types.[1, 2] Key characteristics of metastatic cells include the ability to migrate, invade surrounding tissue, to survive in the periphery, and to attach to and colonize distal sites in the body This progression involves epithelial cells within the primary tumor adopting mesenchymal properties, known as epithelial-to-mesenchymal transition (EMT), a key process in development, wound healing and stem cell biology.[3] EMT is driven by signaling through Wnt, Notch, and TGFβ pathways and is mediated by several transcription factors including Snails, ZEBs, TWISTs and FOXOs, which control expression of genes involved in adhesion, migration, and invasion.[4] The EMT program has been associated with the multistep cascade of the metastatic process,[5] but the relevance of EMT to metastasis remains unclear. The obesity epidemic contributes to the burden of TNBC, as obesity is an established risk factor for development of the disease and may be associated with progression to metastasis.[12,13,14] Emerging features of TNBC, and basal-like and claudin-low TNBC in particular, include aberrant Wnt/β-catenin signaling, stem cell-associated gene expression, and poor morphologic differentiation.[8, 15]
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