Mucin 5AC Serves as the Nexus for β-Catenin/c-Myc Interplay to Promote Glutamine Dependency During Pancreatic Cancer Chemoresistance.
Mucin 5AC Serves as the Nexus for β-Catenin/c-Myc Interplay to Promote Glutamine Dependency During Pancreatic Cancer Chemoresistance.
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DOI：
10.1053/j.gastro.2021.09.017
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发表时间：
2022-01
期刊：
影响因子：
29.4
通讯作者：
Batra SK
中科院分区：
文献类型：
--
作者：
Ganguly K;Bhatia R;Rauth S;Kisling A;Atri P;Thompson C;Vengoji R;Ram Krishn S;Shinde D;Thomas V;Kaur S;Mallya K;Cox JL;Kumar S;Batra SK
胰腺癌(PC)患者的主要临床挑战是代谢适应。含有分子扰动的肿瘤细胞足以满足其增加的合成代谢需求和核苷酸生物合成，从而获得化疗耐药。粘蛋白5AC在恶性胰腺组织中的从头表达促进了癌细胞的干细胞分化，并与患者的不良生存密切相关。通过代谢改变识别MUC5AC相关的化疗耐药驱动因素可能有助于形成新的联合方案。对KrasG12D、Pdx1-Cre(KC)和KrasG12D、Pdx1-Cre、Muc5ac−/−(KCM)小鼠胰腺组织进行热重分析、核糖核酸测序和免疫组织化学分析，探讨MUC5AC在谷氨酰胺分解和吉西他滨耐药中的作用。随后对缺乏MUC5AC的人和小鼠PC细胞进行代谢物通量分析、生化和异种移植研究。用小鼠和人胰腺3D肿瘤模型评价吉西他滨与β-连环蛋白和谷氨酰胺分解抑制剂联合应用的疗效。转录分析表明，高表达MUC5AC的人和小鼠原发PC肿瘤对吉西他滨表现出更高的耐药性，这是由于增强了谷氨酰胺的利用和核苷酸的生物合成。吉西他滨处理导致MUC5AC过表达，导致E-钙粘附素/β-连环蛋白连接中断和β-连环蛋白核移位，从而增加c-Myc的表达，并伴随谷氨酰胺摄取和谷氨酸释放增加。MUC5AC缺失和谷氨酰胺剥夺使人PC细胞对吉西他滨敏感，而在表达MUC5AC的细胞中补充谷氨酰胺可消除这一作用。β-连环蛋白和谷氨酰胺分解抑制剂与吉西他滨联合应用可消除小鼠和人类肿瘤中MUC5AC介导的耐药性。MUC5AC/β-catenin/c-Myc轴可促进PC细胞对谷氨酰胺的摄取和利用，联合吉西他滨可提高PC的治疗效果。在胰腺癌中过度表达的分泌型粘蛋白5AC与化疗耐药有关。因此，针对MUC5AC相关耐药的下游分子以及治疗标准，可能会提高胰腺癌患者的生存率。
A major clinical challenge for pancreatic cancer (PC) patients is metabolic adaptation. Neoplastic cells harboring molecular perturbations suffice for their increased anabolic demand and nucleotide biosynthesis to acquire chemoresistance. The mucin 5AC expressed de novo in malignant pancreas promotes cancer cell stemness and is significantly associated with poor patient survival. Identification of MUC5AC-associated drivers of chemoresistance through metabolic alterations may facilitate sculpting a new combinatorial regimen. The contribution of MUC5AC on glutaminolysis and gemcitabine resistance were examined by TCGA data analysis, RNA sequencing, and immunohistochemistry analysis on pancreatic tissues of KrasG12D; Pdx1-Cre (KC) and KrasG12D; Pdx1-Cre; Muc5ac−/− (KCM) mice. These were followed by metabolite flux assays, biochemical and xenograft studies on MUC5AC-depleted human and murine PC cells. Murine and human pancreatic 3D-tumoroids were used to evaluate gemcitabine’s efficacy in combination with β-catenin and glutaminolysis inhibitors. Transcriptional analysis demonstrated that high MUC5AC-expressing human and autochthonous murine PC tumors exhibit higher resistance to gemcitabine due to enhanced glutamine utilization and nucleotide biosynthesis. Gemcitabine treatment led to MUC5AC overexpression, resulting in disruption of E-Cadherin/β-catenin junctions and the nuclear translocation of β-catenin, which increased c-Myc expression with a concomitant rise in glutamine uptake and glutamate release. MUC5AC-depletion and glutamine deprivation sensitized human PC cells to gemcitabine, which was obviated by glutamine replenishment in MUC5AC-expressing cells. Co-administration of β-catenin and glutaminolysis inhibitors with gemcitabine abrogated the MUC5AC-mediated resistance in murine and human tumoroids. MUC5AC/β-catenin/c-Myc axis increases the uptake and utilization of glutamine in PC cells and co-targeting this axis along with gemcitabine may improve the therapeutic efficacy in PC. Secreted mucin 5AC, overexpressed in pancreatic cancer is responsible for chemoresistance. Therefore, targeting downstream players of MUC5AC-associated drug-resistance along with the standard-of-care may improve the survival of pancreatic cancer patients.
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影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
4
作者：
McCarroll JA;Naim S;Sharbeen G;Russia N;Lee J;Kavallaris M;Goldstein D;Phillips PA
通讯作者：
Phillips PA
DOI：
10.1038/ajg.2016.482
发表时间：
2017-01
期刊：
The American journal of gastroenterology
影响因子：
--
作者：
Kaur S;Smith LM;Patel A;Menning M;Watley DC;Malik SS;Krishn SR;Mallya K;Aithal A;Sasson AR;Johansson SL;Jain M;Singh S;Guha S;Are C;Raimondo M;Hollingsworth MA;Brand RE;Batra SK
通讯作者：
Batra SK
影响因子：
11.2
作者：
Doe MR;Ascano JM;Kaur M;Cole MD
通讯作者：
Cole MD
影响因子：
50.3
作者：
Ishimoto, Takatsugu;Nagano, Osamu;Saya, Hideyuki
通讯作者：
Saya, Hideyuki