作者: de Polo, Anna ; Luthold, Carole ; Zadra, Giorgia ; Ellis, Leigh ; Homsy, Kevin ; Sheridan, Patricia A. ; Photopoulos, Cornelia ; Di Matteo, Anna ; Lalli, Daniela ; Michelotti, Gregory ; Marchionni, Luigi ; Labbé, David P. ; Sabbioneda, Simone ; Syamala, Sudeepa ; Ghigna, Claudia ; Zhao, Xin ; Nguyen, Quang-De ; Liu, Yang ; Spratt, Daniel E. ; Vaira, Valentina ; Chetta, Paolo ; Imada, Eddie L. ; Maga, Giovanni ; Bordeleau, François ; Giunchi, Francesca ; Mucci, Lorelei A. ; Huang, Ying ; Butler, Lisa M. ; Storaci, Alessandra Maria ; Cacciatore, Stefano ; Boufaied, Nadia ; Hallal, Tarek ; Loda, Massimo ; Davicioni, Elai

AbstractCancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation of metabolites that reprogram the tumor microenvironment (TME) and drive cancer could facilitate development of precision nutrition approaches. Using the Hi-MYC prostate cancer mouse model, we demonstrated that an obesogenic high-fat diet (HFD) rich in saturated fats accelerates the development of c-MYC–driven invasive prostate cancer through metabolic rewiring. Although c-MYC modulated key metabolic pathways, interaction with an obesogenic HFD was necessary to induce glycolysis and lactate accumulation in tumors. These metabolic changes were associated with augmented infiltration of CD206+ and PD-L1+ tumor-associated macrophages (TAM) and FOXP3+ regulatory T cells, as well as with the activation of transcriptional programs linked to disease progression and therapy resistance. Lactate itself also stimulated neoangiogenesis and prostate cancer cell migration, which were significantly reduced following treatment with the lactate dehydrogenase inhibitor FX11. In patients with prostate cancer, high saturated fat intake and increased body mass index were associated with tumor glycolytic features that promote the infiltration of M2-like TAMs. Finally, upregulation of lactate dehydrogenase, indicative of a lactagenic phenotype, was associated with a shorter time to biochemical recurrence in independent clinical cohorts. This work identifies cooperation between genetic drivers and systemic metabolism to hijack the TME and promote prostate cancer progression through oncometabolite accumulation. This sets the stage for the assessment of lactate as a prognostic biomarker and supports strategies of dietary intervention and direct lactagenesis blockade in treating advanced prostate cancer.Significance:Lactate accumulation driven by high-fat diet and MYC reprograms the tumor microenvironment and promotes prostate cancer progression, supporting the potential of lactate as a biomarker and therapeutic target in prostate cancer.See related commentary by Frigo, p. 1742

Clinical and Experimental Medicine

Immunometabolic alteration of CD4+ T cells in the pathogenesis of primary Sjögren’s syndrome

Article

作者: Zhao, Lidan ; Peng, Linyi ; Zhou, Jiaxin ; Zhang, Wen ; Chen, Yingying ; Yang, Huaxia ; Fei, Yunyun ; Luo, Xuan ; Li, Mengtao ; Gao, Hui ; Zhao, Yan ; Deng, Chuiwen

AbstractPrimary Sjögren’s syndrome (pSS) is a prevalent autoimmune disorder wherein CD4+ T cells play a pivotal role in its pathogenesis. However, the underlying mechanisms driving the hyperactivity of CD4+ T cells in pSS remain poorly understood. This study aimed to investigate the potential role of immunometabolic alterations in driving the hyperactivity of CD4+ T cells in pSS. We employed Seahorse XF assay to evaluate the metabolic phenotype of CD4+ T cells, conducted flow cytometry to assess the effector function and differentiation of CD4+ T cells and measured the level of intracellular reactive oxygen species (ROS). Additionally, transcriptome sequencing, PCR, and Western blotting were utilized to examine the expression of glycolytic genes. Our investigation revealed that activated CD4+ T cells from pSS patients exhibited elevated aerobic glycolysis, rather than oxidative phosphorylation, resulting in excessive production of IFN-γ and IL-17A. Inhibition of glycolysis by 2-Deoxy-D-glucose reduced the expression of IFN-γ and IL-17A in activated CD4+ T cells and mitigated the differentiation of Th1 and Th17 cells. Furthermore, the expression of glycolytic genes, including CD3E, CD28, PIK3CA, AKT1, mTOR, MYC, LDHA, PFKL, PFKFB3, and PFKFB4, was upregulated in activated CD4+ T cells from pSS patients. Specifically, the expression and activity of LDHA were enhanced, contributing to an increased level of intracellular ROS. Targeting LDHA with FX-11 or inhibiting ROS with N-acetyl-cysteine had a similar effect on reversing the dysfunction of activated CD4+ T cells from pSS patients. Our study unveils heightened aerobic glycolysis in activated CD4+ T cells from pSS patients, and inhibition of glycolysis or its metabolite normalizes the dysfunction of activated CD4+ T cells. These findings suggest that aerobic glycolysis may be a promising therapeutic target for the treatment of pSS.

100 项与 FX11 相关的药物交易

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