Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy

• Published in: Cell 2017-07, Vol.170 (3), p.548-563.e16
• Main Authors: Yu, TaChung, Guo, Fangfang, Yu, Yanan, Sun, Tiantian, Ma, Dan, Han, Jixuan, Qian, Yun, Kryczek, Ilona, Sun, Danfeng, Nagarsheth, Nisha, Chen, Yingxuan, Chen, Haoyan, Hong, Jie, Zou, Weiping, Fang, Jing-Yuan
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Autophagy; Capecitabine - therapeutic use; chemoresistance; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Drug Resistance, Neoplasm; F.nucleatum; Fusobacterium nucleatum - physiology; Gastrointestinal Microbiome; Heterografts; Mice; MicroRNAs - metabolism; miRNA; Neoplasm Transplantation; Platinum Compounds - therapeutic use; Recurrence; Toll-like receptor; Toll-Like Receptors - metabolism; Tumor Microenvironment
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2017.07.008

Gut microbiota are linked to chronic inflammation and carcinogenesis. Chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer patients. Here, we investigated the contribution of gut microbiota to chemoresistance in patients with colorectal cancer. We found that Fusobacterium (F.) nucleatum was abundant in colorectal cancer tissues in patients with recurrence post chemotherapy, and was associated with patient clinicopathological characterisitcs. Furthermore, our bioinformatic and functional studies demonstrated that F. nucleatum promoted colorectal cancer resistance to chemotherapy. Mechanistically, F. nucleatum targeted TLR4 and MYD88 innate immune signaling and specific microRNAs to activate the autophagy pathway and alter colorectal cancer chemotherapeutic response. Thus, F. nucleatum orchestrates a molecular network of the Toll-like receptor, microRNAs, and autophagy to clinically, biologically, and mechanistically control colorectal cancer chemoresistance. Measuring and targeting F. nucleatum and its associated pathway will yield valuable insight into clinical management and may ameliorate colorectal cancer patient outcomes. [Display omitted] •Specific gut microbes track with post-chemotherapy recurrence of colorectal cancer•F. nucleatum orchestrates the Toll-like receptor, microRNAs, and autophagy network to control cancer chemoresistance•Measuring and targeting F. nucleatum may be useful for patient prognosis and management Reducing a specific gut microbe in colorectal cancer patients may improve their response to chemotherapy and reduce cancer recurrence.