ABSTRACT

Obesity causes chronic inflammation and changes in gut microbiome. However, how this contributes to poor survival and therapy resistance in patients with pancreatic cancer remain undetermined. Our current study shows that high fat diet-fed obese pancreatic tumor bearing mice do not respond to standard of care therapy with gemcitabine and paclitaxel when compared to corresponding control diet-fed mice. C57BL6 mice were put on control and high fat diet for 1 month following with pancreatic tumors were implanted in both groups. Microbiome of lean (control) and obese (high fat diet fed) mice was analyzed. Fecal matter transplant from control mice to obese mice sensitized tumors to chemotherapy and demonstrated extensive cell death. Analysis of gut microbiome showed an enrichment of queuosine (Q) producing bacteria in obese mice and an enrichment of S-adenosyl methionine (SAM) producing bacteria in control diet-fed mice. Further, supplementation of obese animals with SAM sensitized pancreatic tumors to chemotherapy. Treatment of pancreatic cancer cells with Q increased PRDX1 involved in oxidative stress protection. In parallel, tumors in obese mice showed increase in CD133⁺ treatment refractory tumor populations compared to control animals. These observations indicated that microbial metabolite Q accumulation in high fat diet-fed mice protected tumors from chemotherapy induced oxidative stress by upregulating PRDX1. This protection could be reversed by treatment with SAM. We conclude that relative concentration of SAM and queuosine in fecal samples of pancreatic cancer patients can be developed as a potential biomarker and therapeutic target in chemotherapy refractory pancreatic cancer.

摘要

肥胖会导致慢性炎症和肠道微生物组的变化。然而，这如何导致胰腺癌患者的低生存率和治疗耐药性仍未确定。我们目前的研究表明，与相应的对照饮食喂养的小鼠相比，高脂肪饮食喂养的肥胖胰腺肿瘤小鼠对吉西他滨和紫杉醇的标准护理治疗没有反应。C57BL6小鼠对照组，高脂饮食1个月后，两组均植入胰腺肿瘤。分析了瘦（对照）和肥胖（喂食高脂肪饮食）小鼠的微生物组。从对照小鼠到肥胖小鼠的粪便移植使肿瘤对化疗敏感，并表现出广泛的细胞死亡。肠道微生物组分析显示，肥胖小鼠体内产生奎奥苷 (Q) 的细菌富集，而对照组饮食喂养的小鼠体内产生 S-腺苷甲硫氨酸 (SAM) 的细菌富集。此外，用SAM补充肥胖动物使胰腺肿瘤对化疗敏感。用 Q 治疗胰腺癌细胞增加了参与氧化应激保护的 PRDX1。同时，肥胖小鼠的肿瘤显示 CD133 增加⁺与对照动物相比，治疗难治性肿瘤群体。这些观察结果表明，高脂饮食喂养的小鼠体内微生物代谢物 Q 的积累通过上调 PRDX1 来保护肿瘤免受化疗诱导的氧化应激。这种保护可以通过 SAM 治疗来逆转。我们得出结论，胰腺癌患者粪便样本中 SAM 和 queuosine 的相对浓度可作为化疗难治性胰腺癌的潜在生物标志物和治疗靶点。