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Metabolic switch regulates lineage plasticity and induces synthetic lethality in triple-negative breast cancer. 代谢开关调节三阴性乳腺癌的细胞系可塑性并诱导合成致死。
Pub Date : 2024-01-02 DOI: 10.1016/j.cmet.2023.12.003
Yingsheng Zhang, Meng-Ju Wu, Wan-Chi Lu, Yi-Chuan Li, Chun Ju Chang, Jer-Yen Yang

Metabolic reprogramming is key for cancer development, yet the mechanism that sustains triple-negative breast cancer (TNBC) cell growth despite deficient pyruvate kinase M2 (PKM2) and tumor glycolysis remains to be determined. Here, we find that deficiency in tumor glycolysis activates a metabolic switch from glycolysis to fatty acid β-oxidation (FAO) to fuel TNBC growth. We show that, in TNBC cells, PKM2 directly interacts with histone methyltransferase EZH2 to coordinately mediate epigenetic silencing of a carnitine transporter, SLC16A9. Inhibition of PKM2 leads to impaired EZH2 recruitment to SLC16A9, and in turn de-represses SLC16A9 expression to increase intracellular carnitine influx, programming TNBC cells to an FAO-dependent and luminal-like cell state. Together, these findings reveal a new metabolic switch that drives TNBC from a metabolically heterogeneous-lineage plastic cell state to an FAO-dependent-lineage committed cell state, where dual targeting of EZH2 and FAO induces potent synthetic lethality in TNBC.

代谢重编程是癌症发展的关键,然而尽管丙酮酸激酶M2(PKM2)和肿瘤糖酵解不足,三阴性乳腺癌(TNBC)细胞仍能维持生长的机制仍有待确定。在这里,我们发现肿瘤糖酵解的缺乏会激活从糖酵解到脂肪酸β-氧化(FAO)的代谢转换,从而促进 TNBC 的生长。我们发现,在 TNBC 细胞中,PKM2 直接与组蛋白甲基转移酶 EZH2 相互作用,协调介导肉碱转运体 SLC16A9 的表观遗传沉默。抑制PKM2会导致EZH2招募到SLC16A9的能力受损,进而抑制SLC16A9的表达,增加细胞内肉碱的流入,使TNBC细胞进入依赖FAO的管腔样细胞状态。这些发现共同揭示了一种新的代谢开关,它能促使 TNBC 从代谢异质性的线型可塑性细胞状态转变为 FAO 依赖性的线型承诺细胞状态,其中 EZH2 和 FAO 的双重靶向能诱导 TNBC 的强效合成致死。
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引用次数: 0
Dietary fructose-mediated adipocyte metabolism drives antitumor CD8+ T cell responses. 膳食果糖介导的脂肪细胞代谢驱动抗肿瘤CD8+T细胞反应。
Pub Date : 2023-12-05 Epub Date: 2023-10-19 DOI: 10.1016/j.cmet.2023.09.011
Yuerong Zhang, Xiaoyan Yu, Rujuan Bao, Haiyan Huang, Chuanjia Gu, Qianming Lv, Qiaoqiao Han, Xian Du, Xu-Yun Zhao, Youqiong Ye, Ren Zhao, Jiayuan Sun, Qiang Zou

Fructose consumption is associated with tumor growth and metastasis in mice, yet its impact on antitumor immune responses remains unclear. Here, we show that dietary fructose modulates adipocyte metabolism to enhance antitumor CD8+ T cell immune responses and control tumor growth. Transcriptional profiling of tumor-infiltrating CD8+ T cells reveals that dietary fructose mediates attenuated transition of CD8+ T cells to terminal exhaustion, leading to a superior antitumor efficacy. High-fructose feeding initiates adipocyte-derived leptin production in an mTORC1-dependent manner, thereby triggering leptin-boosted antitumor CD8+ T cell responses. Importantly, high plasma leptin levels are correlated with elevated plasma fructose concentrations and improved antitumor CD8+ T cell responses in patients with lung cancer. Our study characterizes a critical role for dietary fructose in shaping adipocyte metabolism to prime antitumor CD8+ T cell responses and highlights that the fructose-leptin axis may be harnessed for cancer immunotherapy.

果糖的摄入与小鼠的肿瘤生长和转移有关,但其对抗肿瘤免疫反应的影响尚不清楚。在这里,我们发现膳食果糖调节脂肪细胞代谢,以增强抗肿瘤CD8+T细胞免疫反应并控制肿瘤生长。肿瘤浸润性CD8+T细胞的转录谱分析表明,膳食果糖介导CD8+T淋巴细胞向终末耗竭的减弱过渡,从而产生优异的抗肿瘤功效。高果糖喂养以mTORC1依赖的方式启动脂肪细胞衍生的瘦素的产生,从而触发瘦素增强的抗肿瘤CD8+T细胞反应。重要的是,高血浆瘦素水平与癌症患者血浆果糖浓度升高和抗肿瘤CD8+T细胞反应改善有关。我们的研究表明,膳食果糖在形成脂肪细胞代谢以引发抗肿瘤CD8+T细胞反应中的关键作用,并强调果糖-肽轴可用于癌症免疫疗法。
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引用次数: 0
Redox and detox: Malate shuttle metabolism keeps exhausted T cells fit. 氧化还原和排毒:苹果酸穿梭代谢保持疲惫的T细胞健康。
Pub Date : 2023-12-05 DOI: 10.1016/j.cmet.2023.11.005
Alok Kumar, Greg M Delgoffe

The malate shuttle is known to maintain the balance of NAD+/NADH between the cytosol and mitochondria. However, in Tex cells, it primarily detoxifies ammonia (via GOT1-mediated production of 2-KG in an atypical reaction) and provides longevity to chronic-infection-induced Tex cells against ammonia-induced cell death.

苹果酸穿梭被认为可以维持细胞质和线粒体之间NAD+/NADH的平衡。然而,在特克斯细胞中,它主要解毒氨(通过got1介导的非典型反应产生2-KG),并延长慢性感染诱导的特克斯细胞的寿命,使其免受氨诱导的细胞死亡。
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引用次数: 0
Hyperinsulinemia acts via acinar insulin receptors to initiate pancreatic cancer by increasing digestive enzyme production and inflammation. 高胰岛素血症通过腺泡胰岛素受体通过增加消化酶的产生和炎症来引发胰腺癌症。
Pub Date : 2023-12-05 Epub Date: 2023-10-31 DOI: 10.1016/j.cmet.2023.10.003
Anni M Y Zhang, Yi Han Xia, Jeffrey S H Lin, Ken H Chu, Wei Chuan K Wang, Titine J J Ruiter, Jenny C C Yang, Nan Chen, Justin Chhuor, Shilpa Patil, Haoning Howard Cen, Elizabeth J Rideout, Vincent R Richard, David F Schaeffer, Rene P Zahedi, Christoph H Borchers, James D Johnson, Janel L Kopp

The rising pancreatic cancer incidence due to obesity and type 2 diabetes is closely tied to hyperinsulinemia, an independent cancer risk factor. Previous studies demonstrated reducing insulin production suppressed pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in Kras-mutant mice. However, the pathophysiological and molecular mechanisms remained unknown, and in particular it was unclear whether hyperinsulinemia affected PanIN precursor cells directly or indirectly. Here, we demonstrate that insulin receptors (Insr) in KrasG12D-expressing pancreatic acinar cells are dispensable for glucose homeostasis but necessary for hyperinsulinemia-driven PanIN formation in the context of diet-induced hyperinsulinemia and obesity. Mechanistically, this was attributed to amplified digestive enzyme protein translation, triggering of local inflammation, and PanIN metaplasia in vivo. In vitro, insulin dose-dependently increased acinar-to-ductal metaplasia formation in a trypsin- and Insr-dependent manner. Collectively, our data shed light on the mechanisms connecting obesity-driven hyperinsulinemia and pancreatic cancer development.

由于肥胖和2型糖尿病导致的癌症发病率上升与高胰岛素血症密切相关,高胰岛素血症是癌症的一个独立危险因素。先前的研究表明,减少胰岛素产生可以抑制Kras突变小鼠的胰腺上皮内瘤变(PanIN)癌前病变。然而,其病理生理和分子机制仍然未知,特别是高胰岛素血症是否直接或间接影响PanIN前体细胞尚不清楚。在这里,我们证明了表达KrasG12D的胰腺腺泡细胞中的胰岛素受体(Insr)对于葡萄糖稳态是可有可无的,但对于饮食诱导的高胰岛素血症和肥胖背景下高胰岛素血症驱动的PanIN形成是必要的。从机制上讲,这归因于消化酶蛋白翻译的扩增、局部炎症的触发以及体内PanIN化生。在体外,胰岛素以胰蛋白酶和Insr依赖的方式剂量依赖性地增加腺泡到导管化生的形成。总之,我们的数据揭示了肥胖驱动的高胰岛素血症与胰腺癌症发展之间的机制。
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引用次数: 0
Stress-induced β cell early senescence confers protection against type 1 diabetes. 应激诱导的β细胞早衰对1型糖尿病具有保护作用。
Pub Date : 2023-12-05 Epub Date: 2023-11-09 DOI: 10.1016/j.cmet.2023.10.014
Hugo Lee, Gulcan Semra Sahin, Chien-Wen Chen, Shreyash Sonthalia, Sandra Marín Cañas, Hulya Zeynep Oktay, Alexander T Duckworth, Gabriel Brawerman, Peter J Thompson, Maria Hatzoglou, Decio L Eizirik, Feyza Engin

During the progression of type 1 diabetes (T1D), β cells are exposed to significant stress and, therefore, require adaptive responses to survive. The adaptive mechanisms that can preserve β cell function and survival in the face of autoimmunity remain unclear. Here, we show that the deletion of the unfolded protein response (UPR) genes Atf6α or Ire1α in β cells of non-obese diabetic (NOD) mice prior to insulitis generates a p21-driven early senescence phenotype and alters the β cell secretome that significantly enhances the leukemia inhibitory factor-mediated recruitment of M2 macrophages to islets. Consequently, M2 macrophages promote anti-inflammatory responses and immune surveillance that cause the resolution of islet inflammation, the removal of terminally senesced β cells, the reduction of β cell apoptosis, and protection against T1D. We further demonstrate that the p21-mediated early senescence signature is conserved in the residual β cells of T1D patients. Our findings reveal a previously unrecognized link between β cell UPR and senescence that, if leveraged, may represent a novel preventive strategy for T1D.

在1型糖尿病(T1D)的进展过程中,β细胞暴露于显著的压力下,因此需要适应性反应才能生存。面对自身免疫,能够保护β细胞功能和存活的适应机制尚不清楚。在这里,我们发现非肥胖糖尿病(NOD)小鼠胰岛炎前β细胞中未折叠蛋白反应(UPR)基因Atf6α或Ire1α的缺失会产生p21驱动的早衰表型,并改变β细胞分泌组,从而显著增强白血病抑制因子介导的M2巨噬细胞向胰岛的募集。因此,M2巨噬细胞促进抗炎反应和免疫监测,从而导致胰岛炎症的消退、晚期衰老的β细胞的清除、β细胞凋亡的减少以及对T1D的保护。我们进一步证明了p21介导的早衰信号在T1D患者的残余β细胞中是保守的。我们的发现揭示了β细胞UPR与衰老之间以前未被认识到的联系,如果加以利用,这可能是T1D的一种新的预防策略。
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引用次数: 0
Adipo-glial signaling mediates metabolic adaptation in peripheral nerve regeneration. 脂肪胶质信号介导周围神经再生中的代谢适应。
Pub Date : 2023-12-05 Epub Date: 2023-11-20 DOI: 10.1016/j.cmet.2023.10.017
Venkat Krishnan Sundaram, Vlad Schütza, Nele H Schröter, Aline Backhaus, Annika Bilsing, Lisa Joneck, Anna Seelbach, Clara Mutschler, Jose A Gomez-Sanchez, Erik Schäffner, Eva Ernst Sánchez, Dagmar Akkermann, Christina Paul, Nancy Schwagarus, Silvana Müller, Angela Odle, Gwen Childs, David Ewers, Theresa Kungl, Maren Sitte, Gabriela Salinas, Michael W Sereda, Klaus-Armin Nave, Markus H Schwab, Mario Ost, Peter Arthur-Farraj, Ruth M Stassart, Robert Fledrich

The peripheral nervous system harbors a remarkable potential to regenerate after acute nerve trauma. Full functional recovery, however, is rare and critically depends on peripheral nerve Schwann cells that orchestrate breakdown and resynthesis of myelin and, at the same time, support axonal regrowth. How Schwann cells meet the high metabolic demand required for nerve repair remains poorly understood. We here report that nerve injury induces adipocyte to glial signaling and identify the adipokine leptin as an upstream regulator of glial metabolic adaptation in regeneration. Signal integration by leptin receptors in Schwann cells ensures efficient peripheral nerve repair by adjusting injury-specific catabolic processes in regenerating nerves, including myelin autophagy and mitochondrial respiration. Our findings propose a model according to which acute nerve injury triggers a therapeutically targetable intercellular crosstalk that modulates glial metabolism to provide sufficient energy for successful nerve repair.

周围神经系统在急性神经损伤后具有显著的再生潜力。然而,完全的功能恢复是罕见的,并且严重依赖于周围神经薛旺细胞,这些细胞协调髓磷脂的分解和重新合成,同时支持轴突的再生。雪旺细胞如何满足神经修复所需的高代谢需求仍然知之甚少。我们在此报道,神经损伤诱导脂肪细胞向胶质信号传导,并确定脂肪因子瘦素是再生过程中胶质代谢适应的上游调节剂。雪旺细胞中瘦素受体的信号整合通过调节再生神经中的损伤特异性分解代谢过程,包括髓磷脂自噬和线粒体呼吸,确保有效的周围神经修复。我们的研究结果提出了一个模型,根据该模型,急性神经损伤触发可治疗的细胞间串扰,调节神经胶质代谢,为成功的神经修复提供足够的能量。
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引用次数: 0
Cardiovascular-kidney-metabolic syndrome: A step toward multidisciplinary and inclusive care. 心血管-肾-代谢综合征:迈向多学科和包容性护理的一步。
Pub Date : 2023-12-05 DOI: 10.1016/j.cmet.2023.10.015
Sophie E Claudel, Ashish Verma

In a recent Presidential Advisory report, the American Heart Association (AHA) defined cardiovascular-kidney-metabolic (CKM) syndrome as a spectrum of pathology associated with dysfunctional or excess adiposity and leading to adverse cardiovascular outcomes. Implementing the guidelines set forth by the AHA has the potential to improve population-wide CKM health.

在最近的总统咨询报告中,美国心脏协会(AHA)将心血管-肾-代谢(CKM)综合征定义为与功能失调或过度肥胖相关的一系列病理,并导致不良的心血管结果。实施AHA制定的指导方针有可能改善全人口的CKM健康。
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引用次数: 0
The tRNA-GCN2-FBXO22-axis-mediated mTOR ubiquitination senses amino acid insufficiency. trna - gcn2 - fbxo22轴介导的mTOR泛素化感知氨基酸不足。
Pub Date : 2023-12-05 Epub Date: 2023-11-17 DOI: 10.1016/j.cmet.2023.10.016
Meng-Kai Ge, Cheng Zhang, Na Zhang, Ping He, Hai-Yan Cai, Song Li, Shuai Wu, Xi-Li Chu, Yu-Xue Zhang, Hong-Ming Ma, Li Xia, Shuo Yang, Jian-Xiu Yu, Shi-Ying Yao, Xiao-Long Zhou, Bing Su, Guo-Qiang Chen, Shao-Ming Shen

Mammalian target of rapamycin complex 1 (mTORC1) monitors cellular amino acid changes for function, but the molecular mediators of this process remain to be fully defined. Here, we report that depletion of cellular amino acids, either alone or in combination, leads to the ubiquitination of mTOR, which inhibits mTORC1 kinase activity by preventing substrate recruitment. Mechanistically, amino acid depletion causes accumulation of uncharged tRNAs, thereby stimulating GCN2 to phosphorylate FBXO22, which in turn accrues in the cytoplasm and ubiquitinates mTOR at Lys2066 in a K27-linked manner. Accordingly, mutation of mTOR Lys2066 abolished mTOR ubiquitination in response to amino acid depletion, rendering mTOR insensitive to amino acid starvation both in vitro and in vivo. Collectively, these data reveal a novel mechanism of amino acid sensing by mTORC1 via a previously unknown GCN2-FBXO22-mTOR pathway that is uniquely controlled by uncharged tRNAs.

哺乳动物雷帕霉素靶点复合物1 (mTORC1)监测细胞氨基酸变化的功能,但这一过程的分子介质仍未完全确定。在这里,我们报告了细胞氨基酸的消耗,无论是单独的还是联合的,都会导致mTOR的泛素化,从而通过阻止底物募集来抑制mTORC1激酶的活性。从机制上讲,氨基酸缺失导致未带电trna的积累,从而刺激GCN2磷酸化FBXO22, FBXO22反过来在细胞质中积累,并以k27连接的方式泛素化Lys2066上的mTOR。因此,mTOR Lys2066的突变在氨基酸缺失的情况下消除了mTOR的泛素化,使mTOR在体外和体内对氨基酸饥饿都不敏感。总的来说,这些数据揭示了mTORC1通过以前未知的GCN2-FBXO22-mTOR途径感知氨基酸的新机制,该途径由不带电的trna唯一控制。
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引用次数: 0
Tyrosine catabolism enhances genotoxic chemotherapy by suppressing translesion DNA synthesis in epithelial ovarian cancer. 酪氨酸分解代谢通过抑制上皮性卵巢癌症跨病变DNA合成来增强基因毒性化疗。
Pub Date : 2023-11-07 Epub Date: 2023-10-26 DOI: 10.1016/j.cmet.2023.10.002
Jie Li, Cuimiao Zheng, Qiuwen Mai, Xi Huang, Wenfeng Pan, Jingyi Lu, Zhengfan Chen, Suman Zhang, Chunyu Zhang, Hua Huang, Yangyang Chen, Hongbo Guo, Zhenyin Wu, Chunnuan Deng, Yiting Jiang, Bo Li, Junxiu Liu, Shuzhong Yao, Chaoyun Pan

Amino acid metabolism has been actively investigated as a potential target for antitumor therapy, but how it may alter the response to genotoxic chemotherapy remains largely unknown. Here, we report that the depletion of fumarylacetoacetate hydrolase (FAH), an enzyme that catalyzes the final step of tyrosine catabolism, reduced chemosensitivity in epithelial ovarian cancer (EOC). The expression level of FAH correlated significantly with chemotherapy efficacy in patients with EOC. Mechanistically, under genotoxic chemotherapy, FAH is oxidized at Met308 and translocates to the nucleus, where FAH-mediated tyrosine catabolism predominantly supplies fumarate. FAH-produced fumarate binds directly to REV1, resulting in the suppression of translesion DNA synthesis (TLS) and improved chemosensitivity. Furthermore, in vivo tyrosine supplementation improves sensitivity to genotoxic chemotherapeutics and reduces the occurrence of therapy resistance. Our findings reveal a unique role for tyrosine-derived fumarate in the regulation of TLS and may be exploited to improve genotoxic chemotherapy through dietary tyrosine supplementation.

氨基酸代谢作为抗肿瘤治疗的潜在靶点已被积极研究,但它如何改变对基因毒性化疗的反应在很大程度上仍是未知的。在此,我们报道了富马酸乙酰乙酸水解酶(FAH)的缺失,这种酶催化酪氨酸分解代谢的最后一步,降低了上皮性卵巢癌症(EOC)的化学敏感性。在EOC患者中,FAH的表达水平与化疗疗效显著相关。从机制上讲,在基因毒性化疗下,FAH在Met308被氧化并转移到细胞核,在那里FAH介导的酪氨酸分解代谢主要提供富马酸盐。FAH产生的富马酸盐直接与REV1结合,从而抑制跨病变DNA合成(TLS)并提高化学敏感性。此外,体内补充酪氨酸提高了对基因毒性化疗药物的敏感性,并减少了治疗耐药性的发生。我们的研究结果揭示了酪氨酸衍生的富马酸盐在TLS调节中的独特作用,并可用于通过饮食补充酪氨酸来改善遗传毒性化疗。
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引用次数: 0
The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans. PNPLA3 I148M变体增加了人类的酮体生成,降低了肝脏的新生脂肪生成和线粒体功能。
Pub Date : 2023-11-07 Epub Date: 2023-10-30 DOI: 10.1016/j.cmet.2023.10.008
Panu K Luukkonen, Kimmo Porthan, Noora Ahlholm, Fredrik Rosqvist, Sylvie Dufour, Xian-Man Zhang, Tiina E Lehtimäki, Wenla Seppänen, Marju Orho-Melander, Leanne Hodson, Kitt Falk Petersen, Gerald I Shulman, Hannele Yki-Järvinen

The PNPLA3 I148M variant is the major genetic risk factor for all stages of fatty liver disease, but the underlying pathophysiology remains unclear. We studied the effect of this variant on hepatic metabolism in homozygous carriers and non-carriers under multiple physiological conditions with state-of-the-art stable isotope techniques. After an overnight fast, carriers had higher plasma β-hydroxybutyrate concentrations and lower hepatic de novo lipogenesis (DNL) compared to non-carriers. After a mixed meal, fatty acids were channeled toward ketogenesis in carriers, which was associated with an increase in hepatic mitochondrial redox state. During a ketogenic diet, carriers manifested increased rates of intrahepatic lipolysis, increased plasma β-hydroxybutyrate concentrations, and decreased rates of hepatic mitochondrial citrate synthase flux. These studies demonstrate that homozygous PNPLA3 I148M carriers have hepatic mitochondrial dysfunction leading to reduced DNL and channeling of carbons to ketogenesis. These findings have implications for understanding why the PNPLA3 variant predisposes to progressive liver disease.

PNPLA3 I148M变体是脂肪肝所有阶段的主要遗传风险因素,但其潜在的病理生理学尚不清楚。我们用最先进的稳定同位素技术研究了在多种生理条件下,该变体对纯合携带者和非携带者肝脏代谢的影响。禁食过夜后,与非携带者相比,携带者的血浆β-羟丁酸浓度更高,肝脏新生脂肪生成(DNL)更低。混合餐后,脂肪酸在携带者中被引导向酮体生成,这与肝脏线粒体氧化还原状态的增加有关。在生酮饮食期间,携带者表现出肝内脂解率增加,血浆β-羟丁酸浓度增加,肝线粒体柠檬酸合成酶流量降低。这些研究表明,纯合PNPLA3 I148M携带者具有肝线粒体功能障碍,导致DNL降低,并将碳引导至生酮。这些发现对理解为什么PNPLA3变体易患进行性肝病具有启示意义。
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引用次数: 0
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Cell metabolism
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