美国德克萨斯大学西南医学中心Srinivas Malladi课题组发现，乳腺癌嗜脑细胞内的代谢多样性决定转移适应性。相关论文于2022年1月4日发表在《细胞—代谢》杂志上。

据研究人员介绍，HER2+乳腺癌患者会出现同步性（S-BM）、潜伏性（Lat）或隐匿性（M-BM）的脑转移。然而，在一个远端器官内，类似肿瘤类型的扩散肿瘤细胞之间的不同转移适应性的基础仍然未知。

研究人员采用脑转移模型表明，脑转移细胞内的代谢多样性和可塑性决定转移的适应性。侵袭性转移细胞分泌的乳酸或对携带Lat细胞的小鼠补充乳酸限制了先天免疫监视并引发明显的转移。削弱S-BM中的乳酸代谢会阻碍转移，而M-BM则适应并作为残余疾病存活。与S-BM相反，Lat和M-BM在与先天免疫监视的平衡中生存，氧化谷氨酰胺，并通过阴离子氨基酸转运体xCT维持细胞的氧化还原平衡。

此外，与HER2+乳腺癌患者的原发肿瘤相比，匹配的M-BM脑转移样本中xCT的表达明显更高。在这些临床前模型中，抑制xCT功能可以减弱残余疾病和复发。

附：英文原文

Title: Metabolic diversity within breast cancer brain-tropic cells determines metastatic fitness

Author: Pravat Kumar Parida, Mauricio Marquez-Palencia, Vidhya Nair, Akash K. Kaushik, Kangsan Kim, Jessica Sudderth, Eduardo Quesada-Diaz, Ambar Cajigas, Vamsidhara Vemireddy, Paula I. Gonzalez-Ericsson, Melinda E. Sanders, Bret C. Mobley, Kenneth Huffman, Sunati Sahoo, Prasanna Alluri, Cheryl Lewis, Yan Peng, Robert M. Bachoo, Carlos L. Arteaga, Ariella B. Hanker, Ralph J. DeBerardinis, Srinivas Malladi

Issue&Volume: 2022/01/04

Abstract: HER2+ breast cancer patients are presented with either synchronous (S-BM), latent (Lat), or metachronous (M-BM) brain metastases. However, the basis for disparate metastatic fitness among disseminated tumor cells of similar oncotype within a distal organ remains unknown. Here, employing brain metastatic models, we show that metabolic diversity and plasticity within brain-tropic cells determine metastatic fitness. Lactate secreted by aggressive metastatic cells or lactate supplementation to mice bearing Lat cells limits innate immunosurveillance and triggers overt metastasis. Attenuating lactate metabolism in S-BM impedes metastasis, while M-BM adapt and survive as residual disease. In contrast to S-BM, Lat and M-BM survive in equilibrium with innate immunosurveillance, oxidize glutamine, and maintain cellular redox homeostasis through the anionic amino acid transporter xCT. Moreover, xCT expression is significantly higher in matched M-BM brain metastatic samples compared to primary tumors from HER2+ breast cancer patients. Inhibiting xCT function attenuates residual disease and recurrence in these preclinical models.

DOI: 10.1016/j.cmet.2021.12.001

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00620-3