O'Flanagan Ciara H, Rossi Emily L, McDonell Shannon B, Chen Xuewen, Tsai Yi-Hsuan, Parker Joel S, Usary Jerry, Perou Charles M, Hursting Stephen D
Department of Nutrition, University of North Carolina, Chapel Hill, NC 27517 USA.
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27517 USA.
NPJ Breast Cancer. 2017 Jul 17;3:26. doi: 10.1038/s41523-017-0027-5. eCollection 2017.
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-Wnt through serial passaging of our previously described, nonmetastatic, claudin-low M-Wnt cell line. metM-Wnt 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-Wnt 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-Wnt 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-Wnt 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.
绝大多数与癌症相关的死亡是由转移性疾病导致的，即原发性肿瘤细胞扩散并在体内远处部位定植。三阴性乳腺癌通常表现出异常的Wnt信号传导，缺乏有效的靶向治疗，并且与其他乳腺癌亚型相比，更有可能复发和转移。我们通过对之前描述的非转移性、claudin低表达的M-Wnt细胞系进行连续传代，建立了一种Wnt驱动的三阴性乳腺癌肺转移模型（metM-Wnt）。metM-Wnt细胞表现出上皮-间质转化的特征（如侵袭性增加），同时伴有一些重新上皮化现象（如黏附增加、紧密集落形成、E-钙黏蛋白表达增加以及波形蛋白和纤连蛋白表达减少）。当原位移植到同基因小鼠体内时，metM-Wnt细胞很容易形成肿瘤并在体内发生转移，与非肥胖小鼠相比，肥胖小鼠的肿瘤生长和转移增强。基因表达分析显示，与M-Wnt细胞相比，metM-Wnt细胞中有几个基因和信号通路发生了改变，包括多个与上皮-间质转化、能量代谢和炎症相关的基因。此外，肥胖引起了显著的转录组变化，尤其是在代谢途径方面。代谢通量分析表明，metM-Wnt细胞具有更大的代谢可塑性，相对于M-Wnt细胞，其线粒体和糖酵解能量增强。在第二个三阴性乳腺癌进展系列M6和M6C细胞中也发现了类似的代谢谱。这些发现表明，代谢重编程是三阴性乳腺癌转移潜能的一个特征。因此，针对与转移相关的代谢紊乱进行靶向治疗，可能是减轻转移性三阴性乳腺癌负担的一种新策略，尤其是在肥胖女性中。
