Background & Aims

A major clinical challenge for patients with pancreatic cancer (PC) 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 the sculpting of a new combinatorial regimen.

Methods

The contributions of MUC5AC to glutaminolysis and gemcitabine resistance were examined by The Cancer Genome Atlas data analysis, RNA sequencing, and immunohistochemistry analysis on pancreatic tissues of Kras^G12D;Pdx1-Cre (KC) and Kras^G12D;Pdx1-Cre;Muc5ac^–/– mice. These were followed by metabolite flux assays as well as biochemical and xenograft studies on MUC5AC-depleted human and murine PC cells. Murine and human pancreatic 3-dimensional tumoroids were used to evaluate the efficacy of gemcitabine in combination with β-catenin and glutaminolysis inhibitors.

Results

Transcriptional analysis showed that high MUC5AC-expressing human and autochthonous murine PC tumors exhibit higher resistance to gemcitabine because of enhanced glutamine use 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. Coadministration of β-catenin and glutaminolysis inhibitors with gemcitabine abrogated the MUC5AC-mediated resistance in murine and human tumoroids.

Conclusions

The MUC5AC/β-catenin/c-Myc axis increases the uptake and use of glutamine in PC cells, and cotargeting this axis along with gemcitabine may improve therapeutic efficacy in PC.

中文翻译：

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Mucin 5AC 作为 β-Catenin/c-Myc 相互作用的纽带，促进胰腺癌化疗耐药期间的谷氨酰胺依赖性

 背景与目标

胰腺癌（PC）患者面临的主要临床挑战是​​代谢适应。具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以获得化疗耐药性。恶性胰腺中从头表达的粘蛋白 5AC 可促进癌细胞干细胞性，并与患者生存率低下显着相关。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制定新的组合方案。

 方法

通过癌症基因组图谱数据分析、RNA 测序和 Kras ^G12D ;Pdx1-Cre (KC) 和 Kras ^G12D ;Pdx1-Cre;Muc5ac 胰腺组织的免疫组织化学分析，检查了 MUC5AC 对谷氨酰胺分解和吉西他滨耐药性的贡献^-/–老鼠。随后对 MUC5AC 耗尽的人和鼠 PC 细胞进行代谢通量测定以及生化和异种移植研究。使用小鼠和人类胰腺 3 维肿瘤样体来评估吉西他滨与 β-连环蛋白和谷氨酰胺分解抑制剂联合使用的疗效。

 结果

转录分析表明，高表达 MUC5AC 的人类和本土鼠 PC 肿瘤由于谷氨酰胺的利用和核苷酸生物合成增强，对吉西他滨表现出更高的耐药性。吉西他滨治疗导致 MUC5AC 过度表达，导致 E-钙粘蛋白/β-连环蛋白连接破坏和 β-连环蛋白核转位，从而增加 c-Myc 表达，同时谷氨酰胺摄取和谷氨酸释放增加。 MUC5AC 耗竭和谷氨酰胺剥夺使人 PC 细胞对吉西他滨敏感，但在表达 MUC5AC 的细胞中补充谷氨酰胺可以避免这种情况。 β-连环蛋白和谷氨酰胺分解抑制剂与吉西他滨的共同给药消除了小鼠和人类肿瘤样细胞中 MUC5AC 介导的耐药性。

 结论

MUC5AC/β-catenin/c-Myc 轴增加 PC 细胞中谷氨酰胺的摄取和利用，将该轴与吉西他滨共同靶向可能会提高 PC 的治疗效果。