Acetyl-Coenzyme A Synthetase 2 Potentiates Macropinocytosis and Muscle Wasting Through Metabolic Reprogramming in Pancreatic Cancer.
Acetyl-Coenzyme A Synthetase 2 Potentiates Macropinocytosis and Muscle Wasting Through Metabolic Reprogramming in Pancreatic Cancer.
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DOI：
10.1053/j.gastro.2022.06.058
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发表时间：
2022-11
期刊：
影响因子：
29.4
通讯作者：
中科院分区：
文献类型：
--
作者：
快速失调，也称为恶病质，和代谢重编程是胰腺癌的两个标志。ACSS 2是一种乙酰辅酶A合成酶，有助于脂质合成和表观遗传重编程。然而，ACSS 2在胰腺癌中的非选择性巨胞饮和癌症恶病质中的作用仍然是难以捉摸的。在这项研究中，我们证明ACSS 2通过胰腺癌的代谢重编程增强巨胞饮和肌肉萎缩。使用人胰腺癌患者样品分析ACSS 2的临床意义。利用CRISPR-Cas9系统建立ACSS 2敲除细胞。分析了来自基因工程小鼠模型的单细胞RNA测序数据。葡聚糖摄取试验测定巨噬细胞指数。进行ChIP测定以验证转录激活。在原位异种移植模型中检查ACSS 2介导的肿瘤进展和肌肉萎缩。代谢应激诱导ACSS 2表达，与胰腺癌预后不良相关。ACSS 2敲除在2D和3D模型中显著抑制细胞增殖。巨胞饮相关基因在肿瘤组织中上调，并与预后不良相关。ACSS 2敲除抑制巨胞饮作用。我们鉴定ZIP 4为ACSS 2的下游靶标，并且ZIP 4的敲低逆转ACSS 2诱导的巨胞饮。ACSS 2通过ETV 4介导的转录激活上调ZIP 4。ZIP 4通过CREB激活的SDC 1和DNM 2诱导巨胞饮。同时，ZIP 4通过GSK 3 β介导的TRAIL分泌驱动肌肉萎缩和恶病质。ACSS 2敲除在原位小鼠模型中减轻肌肉萎缩并延长存活。ACSS 2介导的代谢重编程激活ZIP 4通路，并通过SDC 1/DNM 2促进巨胞饮，并通过GSK 3 β/TRAIL轴驱动肌肉萎缩，这可能为胰腺癌中的巨胞饮提供额外的营养。ACSS 2通过ETV 4/ZIP 4介导的代谢重编程促进巨胞饮和肌肉萎缩，这提供了额外的营养物质来支持胰腺癌中的肿瘤生长。
Rapid deconditioning, also called cachexia, and metabolic reprogramming are two hallmarks of pancreatic cancer. ACSS2 is an acetyl-coA synthetase that contributes to lipid synthesis and epigenetic reprogramming. However, the role of ACSS2 on the non-selective macropinocytosis and cancer cachexia in pancreatic cancer remains elusive. In this study, we demonstrate that ACSS2 potentiates macropinocytosis and muscle wasting through metabolic reprogramming in pancreatic cancer. Clinical significance of ACSS2 was analyzed using human pancreatic cancer patient samples. ACSS2 knockout cells were established utilizing CRISPR-Cas9 system. Single-cell RNA sequencing data from genetically engineered mouse models was analyzed. Macropinocytotic index was evaluated by dextran uptake assay. ChIP assay was performed to validate transcriptional activation. ACSS2 mediated tumor progression and muscle wasting were examined in orthotopic xenograft models. Metabolic stress induced ACSS2 expression, which is associated with worse prognosis in pancreatic cancer. ACSS2 knockout significantly suppressed cell proliferation in 2D and 3D models. Macropinocytosis associated genes are upregulated in tumor tissues and are correlated to worse prognosis. ACSS2 knockout inhibited macropinocytosis. We identified ZIP4 as a downstream target of ACSS2, and knockdown of ZIP4 reversed ACSS2 induced macropinocytosis. ACSS2 upregulated ZIP4 through ETV4 mediated transcriptional activation. ZIP4 induces macropinocytosis through CREB activated SDC1 and DNM2. Meanwhile, ZIP4 drives muscle wasting and cachexia via GSK3β mediated secretion of TRAIL. ACSS2 knockout attenuated muscle wasting and extended survival in orthotopic mouse models. ACSS2-mediated metabolic reprogramming activates ZIP4 pathway, and promotes macropinocytosis via SDC1/DNM2 and drives muscle wasting through GSK3β/TRAIL axis, which potentially provides additional nutrients for macropinocytosis in pancreatic cancer. ACSS2 promotes macropinocytosis and muscle wasting through ETV4/ZIP4 mediated metabolic reprogramming, which provides additional nutrients to support tumor growth in pancreatic cancer.
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影响因子：
14.8
作者：
通讯作者：
--
DOI：
10.1002/jcsm.12346
发表时间：
2018-12
期刊：
Journal of cachexia, sarcopenia and muscle
影响因子：
--
作者：
Kandarian SC;Nosacka RL;Delitto AE;Judge AR;Judge SM;Ganey JD;Moreira JD;Jackman RW
通讯作者：
Jackman RW
DOI：
10.1002/jcsm.12642
发表时间：
2020-12
期刊：
Journal of cachexia, sarcopenia and muscle
影响因子：
--
作者：
Huot JR;Pin F;Narasimhan A;Novinger LJ;Keith AS;Zimmers TA;Willis MS;Bonetto A
通讯作者：
Bonetto A
影响因子：
29.4
作者：
Liu M;Zhang Y;Yang J;Cui X;Zhou Z;Zhan H;Ding K;Tian X;Yang Z;Fung KA;Edil BH;Postier RG;Bronze MS;Fernandez-Zapico ME;Stemmler MP;Brabletz T;Li YP;Houchen CW;Li M
通讯作者：
Li M
影响因子：
8.8
作者：
Michalopoulou, Evdokia;Auciello, Francesca R.;Kamphorst, Jurre J.
通讯作者：
Kamphorst, Jurre J.