ABSTRACT

Intratumor microbiome shapes the immune system and influences the outcome of various tumors. Porphyromonas gingivalis (P. gingivalis), the keystone periodontal pathogen, is highly epidemically connected with pancreatic cancer (PC). However, its causative role and the underlining mechanism in promoting PC oncogenesis remain unclear. Here, we illustrated the landscape of intratumor microbiome and its bacterial correlation with oral cavity in PC patients, where P. gingivalis presented both in the oral cavity and tumor tissues. When exposed to P. gingivalis, tumor development was accelerated in orthotopic and subcutaneous PC mouse model, and the cancerous pancreas exhibited a neutrophils-dominated proinflammatory tumor microenvironment. Mechanistically, the intratumoral P. gingivalis promoted PC progression via elevating the secretion of neutrophilic chemokines and neutrophil elastase (NE). Collectively, our study disclosed the bacterial link between periodontitis and PC, and revealed a previously unrecognized mechanism of P. gingivalis in PC pathophysiology, hinting at therapeutic implications.

摘要

肿瘤内微生物组塑造免疫系统并影响各种肿瘤的结果。牙龈卟啉单胞菌( P. gingivalis ) 是牙周病的主要病原体，与胰腺癌 (PC) 具有高度流行相关性。然而，其在促进 PC 肿瘤发生中的致病作用和强调机制仍不清楚。在这里，我们展示了 PC 患者肿瘤内微生物组的景观及其与口腔的细菌相关性，其中P. gingivalis同时存在于口腔和肿瘤组织中。当暴露于牙龈卟啉单胞菌时，原位和皮下PC小鼠模型中肿瘤发展加速，癌变胰腺表现出以中性粒细胞为主的促炎性肿瘤微环境。从机制上讲，瘤内牙龈卟啉单胞菌通过提高中性粒细胞趋化因子和中性粒细胞弹性蛋白酶 (NE) 的分泌来促进 PC 进展。总的来说，我们的研究揭示了牙周炎和 PC 之间的细菌联系，并揭示了P. gingivalis在 PC 病理生理学中以前未被认识的机制，暗示了治疗意义。