Department of Medicine, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Department of Surgery, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Department of Pathology, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Gastroenterology. 2022 Nov;163(5):1281-1293.e1. doi: 10.1053/j.gastro.2022.06.058. Epub 2022 Jun 28.
BACKGROUND & AIMS: Rapid deconditioning, also called cachexia, and metabolic reprogramming are two hallmarks of pancreatic cancer. Acetyl-coenzyme A synthetase short-chain family member 2 (ACSS2) is an acetyl-enzyme A synthetase that contributes to lipid synthesis and epigenetic reprogramming. However, the role of ACSS2 on the nonselective 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 samples from patients with pancreatic cancer. ACSS2-knockout cells were established using the clustered regularly interspaced short palindromic repeats-associated protein 9 system. Single-cell RNA sequencing data from genetically engineered mouse models was analyzed. The macropinocytotic index was evaluated by dextran uptake assay. Chromatin immunoprecipitation 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 2-dimensional and 3-dimensional models. Macropinocytosis-associated genes are upregulated in tumor tissues and are correlated with worse prognosis. ACSS2 knockout inhibited macropinocytosis. We identified Zrt- and Irt-like protein 4 (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 cyclic adenosine monophosphate response element-binding protein-activated syndecan 1 (SDC1) and dynamin 2 (DNM2). Meanwhile, ZIP4 drives muscle wasting and cachexia via glycogen synthase kinase-β (GSK3β)-mediated secretion of tumor necrosis factor superfamily member 10 (TRAIL or TNFSF10). ACSS2 knockout attenuated muscle wasting and extended survival in orthotopic mouse models.
ACSS2-mediated metabolic reprogramming activates the ZIP4 pathway, and promotes macropinocytosis via SDC1/DNM2 and drives muscle wasting through the GSK3β/TRAIL axis, which potentially provides additional nutrients for macropinocytosis in pancreatic cancer.
快速去适应（亦称恶病质）和代谢重编程是胰腺癌的两个特征。乙酰辅酶 A 合成酶短链家族成员 2（ACSS2）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，ACSS2 在非选择性巨胞饮作用和胰腺癌恶病质中的作用仍不清楚。在本研究中，我们证明 ACSS2 通过代谢重编程促进胰腺癌中的巨胞饮作用和肌肉消耗。
使用胰腺癌患者的样本分析 ACSS2 的临床意义。使用簇状规则间隔短回文重复相关蛋白 9 系统建立 ACSS2 敲除细胞。分析基因工程小鼠模型的单细胞 RNA 测序数据。通过葡聚糖摄取测定评估巨胞饮指数。进行染色质免疫沉淀测定以验证转录激活。在原位异种移植模型中检查 ACSS2 介导的肿瘤进展和肌肉消耗。
代谢应激诱导 ACSS2 表达，与胰腺癌预后不良相关。ACSS2 敲除显著抑制 2 维和 3 维模型中的细胞增殖。肿瘤组织中上调的巨胞饮相关基因与预后不良相关。ACSS2 敲除抑制巨胞饮作用。我们确定 Zrt 和 Irt 样蛋白 4（ZIP4）为 ACSS2 的下游靶标，并且 ZIP4 的敲低逆转了 ACSS2 诱导的巨胞饮作用。ACSS2 通过 ETV4 介导的转录激活上调 ZIP4。ZIP4 通过环磷酸腺苷反应元件结合蛋白激活的 syndecan 1（SDC1）和 dynamin 2（DNM2）诱导巨胞饮作用。同时，ZIP4 通过糖原合酶激酶-β（GSK3β）介导的肿瘤坏死因子超家族成员 10（TRAIL 或 TNFSF10）的分泌驱动肌肉消耗和恶病质。ACSS2 敲除在原位小鼠模型中减轻肌肉消耗并延长生存。
ACSS2 介导的代谢重编程激活 ZIP4 途径，通过 SDC1/DNM2 促进巨胞饮作用，并通过 GSK3β/TRAIL 轴驱动肌肉消耗，这可能为胰腺癌中的巨胞饮作用提供额外的营养物质。
