A high- fat diet promotes cancer progression by inducing gut microbiota-mediated leucine production and PMN- MDSC differentiation

• 成果类型: Article
• 署名作者: Chen, Jiewen; Liu, Xiyuan; Zou, Yi; Gong, Junli; Ge, Zhenhuang; Lin, Xiaorong; Zhang, Wei; Huang, Hongyan; Zhao, Jianli; Saw, Phei Er; Lu, Yongjun; Hu, Hai; Song, Erwei
• 署名单位: Sun Yat Sen University; Sun Yat Sen University; Sun Yat Sen University; Sun Yat Sen University; Southern Medical University - China; Sun Yat Sen University; Sun Yat Sen University; Southern Medical University - China
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11162
• DOI: 10.1073/pnas.2306776121
• 发表日期: 2024-05-14
• 关键词: breast-cancer; obesity; fructose; immunity

摘要

A high - fat diet (HFD) is a high - risk factor for the malignant progression of cancers through the disruption of the intestinal microbiota. However, the role of the HFDrelated gut microbiota in cancer development remains unclear. This study found that obesity and obesity - related gut microbiota were associated with poor prognosis and advanced clinicopathological status in female patients with breast cancer. To investigate the impact of HFDassociated gut microbiota on cancer progression, we established various models, including HFD feeding, fecal microbiota transplantation, antibiotic feeding, and bacterial gavage, in tumor - bearing mice. HFDrelated microbiota promotes cancer progression by generating polymorphonuclear myeloidderived suppressor cells (PMNMDSCs). Mechanistically, the HFD microbiota released abundant leucine, which activated the mTORC1 signaling pathway in myeloid progenitors for PMN - MDSC differentiation. Clinically, the elevated leucine level in the peripheral blood induced by the HFD microbiota was correlated with abundant tumoral PMN - MDSC infiltration and poor clinical outcomes in female patients with breast cancer. These findings revealed that the gut-bone marrow-tumor axis is involved in HFDmediated cancer progression and opens a broad avenue for anticancer therapeutic strategies by targeting the aberrant metabolism of the gut microbiota.