Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy

Abstract

SUMMARY 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, micro-RNAs, 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.

MEGF6 Promotes the Epithelial-to-Mesenchymal Transition via the TGFβ/SMAD Signaling Pathway in Colorectal Cancer Metastasis

“…Adjuvant chemotherapy for CRC usually includes fluorouracil (5-FU), which is the most widely used chemotherapeutic agent for the treatment of this disease. Specifically, combination therapy of 5-FU with oxaliplatin, irinotecan, or capecitabine has been extensively used to treat CRC [5], and has been successful in the majority of patients with advanced disease [6]. However, these patients often experience recurrence caused by drug resistance, and the 5-year survival rate is lower than 10% in patients with advanced CRC [7].…”

Bacterial snack attack deactivates a drug

“…For instance, people who have colorectal cancer often harbour high numbers of tumour-associated Fuso bacterium nucleatum bacteria, and this association is linked to poor clinical prognosis 6 . This bacterium can trigger the activation of a pathway in colorectal-cancer cells that results in the tumour developing resistance to the drugs fluorouracil and oxaliplatin 7 .…”

“…Such optimization has conventionally been achieved either by testing combinations of variables manually or by using machinelearning techniques. Each of these approaches has advantages in different situations and both were instrumental in the discovery of the Higgs boson 7,8 in 2012.…”

Role of Gut Microbiota in the Development and Treatment of Colorectal Cancer

“…Mechanistically, F. nucleatum targeted TLR4 and MYD88 innate immune signaling and specific microRNAs to activate the autophagy pathway and alter CRC chemotherapeutic response [42]. And oral probiotic Lactobacillus casei variety rhamnosus (Lcr35) prevented FOLFOX-induced intestinal mucositis in CRC-bearing mice [42].…”