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Using tumor-bearing mouse models (diet, fecal transplantation, antibiotics, gavage), HFD microbiota promotes progression by generating PMN-MDSCs via microbiota-derived leucine and mTORC1 signaling. Elevated peripheral leucine correlates with PMN-MDSC infiltration and worse outcomes.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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question does the study address about high-fat diets and cancer?","Question",{"text":63,"@type":64},"It investigates how HFD-related gut microbiota contributes to cancer progression and clarifies the underlying mechanism linking diet, microbiota changes, and tumor outcomes.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How does the HFD-related gut microbiota promote cancer progression in the models?",{"text":68,"@type":64},"It promotes progression by generating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) through leucine release that activates mTORC1 signaling in myeloid progenitors.",{"name":70,"@type":61,"acceptedAnswer":71},"What clinical association is reported for leucine and PMN-MDSC in patients?",{"text":72,"@type":64},"In female breast cancer patients, elevated peripheral blood leucine induced by HFD microbiota correlates with increased tumoral PMN-MDSC infiltration and poorer clinical 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microbiota–mediated leucine production and PMN-MDSC differentiation  \nJiewen Chena, b,c,1, Xiyuan Liud,1, Yi Zoud, Junli Gongd,2, Zhenhuang Ged , Xiaorong Line, Wei Zhangf, Hongyan Huangg, Jianli Zhaoa, Phei Er Sawa , Yongjun Lud,3, Hai Hua,f,3, and Erwei Songa, b,3  \nEdited by Laurence Zitvogel, Institut Gustave Roussy-France, VILLEJUIF Cedex, France; received May 9, 2023; accepted February 16, 2024 by Editorial Board Member Anton Berns  \nA 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 HFD-related 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 HFD-associated gut microbiota on cancer progression, we established various models, including HFD feeding, fecal microbiota transplantation, antibiotic feeding, and bacterial gavage, in tumor-bearing mice. HFD-related microbiota promotes cancer progression by generating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). 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 HFD-mediated cancer progression and opens a broad avenue for anticancer therapeutic strategies by targeting the aberrant metabolism of the gut microbiota.  \nhigh-fat diet | gut microbiota | breast cancer | myeloid-derived suppressor cells  \nHigh-fat intake and obesity rates are increasing globally. Notably, >33% of the adult American population is overweight or obese due to their high fat intake (1, 2) . This population is also rapidly increasing in Asia (3). Consistent with this, the incidence of malignancy is gradually increasing, and a high-fat diet (HFD) and obesity are now considered critical but modifiable risk factors for several malignancies, including breast cancer, melanoma, and liver cancer (4–6). For example, obesity associated with dietary fat has been associated with breast cancer development in postmenopausal women (6), and approximately 30% of breast cancers in women are preventable by weight control, indicating an essential role of obesity in tumorigenesis (7) . However, the mechanistic link between obesity and cancer development remains unclear.  \nEmerging data suggest that an HFD or obesity induces cancer by accumulating adipose tissue or alternating gut microbiota, leading to systemic changes in steroid hormones and adipokines production, metabolic disorders, and chronic subclinical inflammation (8–10) . In addition, excessive adipose tissue accumulation may alter the immune microenvironment, causing adipose inflammation, immune cell infiltration, and massive production of adipokines, cytokines, and proteases that influence immune cell function (11) . Notably, aberrant gut microbiota is also involved in drug resistance to chemotherapy, immune checkpoint inhibitors, and tyrosine kinase inhibitors in several nondigestive cancer types, such as breast cancer, lung cancer, and melanoma (12–15) . Typically, patients with advanced-stage breast cancer have a higher abundance of Clostridium and Lachnospiraceaespp. in their feces than those with early-stage breast cancer, supporting the interplay between the gut microbiota and breast cancer progression (16) . Furthermore, employing shotgun metagenomics, Terrisse et al. discovered that gut dysbiosis develops as breast cancer advanc","cbCaimSS9eqpVtNL","https://ap.wps.com/l/cbCaimSS9eqpVtNL","pdf",2124402,12,"English","# Background\n## Obesity, HFD, and cancer risk\n## Gut microbiota dysbiosis and therapy resistance\n# Study Rationale and Hypothesis\n# Findings and Mechanistic Model\n## Leucine production and mTORC1 activation\n## PMN-MDSC differentiation and the gut–bone marrow–tumor axis\n# Clinical Correlations and Therapeutic Implications\n# Declarations and Publication Notes","[{\"question\":\"What question does the study address about high-fat diets and cancer?\",\"answer\":\"It investigates how HFD-related gut microbiota contributes to cancer progression and clarifies the underlying mechanism linking diet, microbiota changes, and tumor outcomes.\"},{\"question\":\"How does the HFD-related gut microbiota promote cancer progression in the models?\",\"answer\":\"It promotes progression by generating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) through leucine release that activates mTORC1 signaling in myeloid progenitors.\"},{\"question\":\"What clinical association is reported for leucine and PMN-MDSC in patients?\",\"answer\":\"In female breast cancer patients, elevated peripheral blood leucine induced by HFD microbiota correlates with increased tumoral PMN-MDSC infiltration and poorer clinical outcomes.\"}]","A high-fat diet promotes cancer progression by inducing gut microbiota–mediated leucine production and PMN-MDSC differentiation | PDF",1790002168]