Metabolic reprogramming underlies metastatic potential in an obesity-responsive murine model of metastatic triple negative breast cancer

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.

Signals from the Adipose Microenvironment and the Obesity–Cancer Link—A Systematic Review

“…O’Flanagan et al has demonstrated that obesity enhances the development and metastatic spread of orthotopically transplanted metM-Wnt lung cells, a triple negative breast cancer (TNBC) cell line that metastasizes to the lung (25). Pascual et al also showed that diet-induced obesity increases the metastatic potential of several types of cancer cells, including oral squamous cell carcinoma, melanoma, luminal breast cancer, bladder cancer and small cell lung carcinoma, in a CD36-dependent manner (26).…”

Simultaneous targeting therapy for lung metastasis and breast tumor by blocking the NF-κB signaling pathway using Celastrol-loaded micelles

“…Most deaths from breast tumor are due to metastatic disease (O'Flanagan et al., 2017 ) and the five-year survival rate for advanced or metastasized breast tumor is only 26%. For many patients, metastasis has already occurred when tumor is detected (Klein, 2009 ; Ullah et al., 2017 ).…”

Tumor-extrinsic discoidin domain receptor 1 promotes mammary tumor growth by regulating adipose stromal interleukin 6 production in mice

“…The AT-3 cell line was derived from an MMTV-PyMT transgenic mouse mammary tumor 26 , whereas M-Wnt was established from an MMTV-Wnt-1 transgenic mouse mammary tumor 27 .We chose these two tumor cell lines because both are syngeneic with C57BL/6 mice and have been used as models for triple negative breast cancer [28][29][30][31] . Tumor sizes were assessed by caliper measurement over a period of 4-7 weeks, and tumors were weighed upon harvest.…”