Fusobacterium Nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy

Cell. 2017 Jul 27;170(3):548-563.e16. doi: 10.1016/j.cell.2017.07.008.

Abstract

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.

Keywords: Colorectal cancer; F.nucleatum; Toll-like receptor; autophagy; chemoresistance; miRNA; recurrence.

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use
  • Autophagy*
  • Capecitabine / therapeutic use
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology*
  • Drug Resistance, Neoplasm
  • Fusobacterium nucleatum / physiology*
  • Gastrointestinal Microbiome*
  • Heterografts
  • Mice
  • MicroRNAs / metabolism
  • Neoplasm Transplantation
  • Platinum Compounds / therapeutic use
  • Recurrence
  • Toll-Like Receptors / metabolism
  • Tumor Microenvironment

Substances

  • Antineoplastic Agents
  • MIRN18A microRNA, human
  • MIRN4802 microRNA, human
  • MicroRNAs
  • Platinum Compounds
  • Toll-Like Receptors
  • Capecitabine