Proinflammatory and Cancer-Promoting Pathobiont Fusobacterium nucleatum Directly Targets Colorectal Cancer Stem Cells

Virve Cavallucci, Ivana Palucci, Marco Fidaleo, Antonella Mercuri, Letizia Masi, Valeria Emoli, Giada Bianchetti, Micol Eleonora Fiori, Gilad Bachrach, Franco Scaldaferri, Giuseppe Maulucci, Giovanni Delogu, Giovambattista Pani*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Intestinal bacterial communities participate in gut homeostasis and are recognized as crucial in bowel inflammation and colorectal cancer (CRC). Fusobacterium nucleatum (Fn), a pathobiont of the oral microflora, has recently emerged as a CRC-associated microbe linked to disease progression, metastasis, and a poor clinical outcome; however, the primary cellular and/or microenvironmental targets of this agent remain elusive. We report here that Fn directly targets putative colorectal cancer stem cells (CR-CSCs), a tumor cell subset endowed with cancer re-initiating capacity after surgery and chemotherapy. A patient-derived CSC line, highly enriched (70%) for the stem marker CD133, was expanded as tumor spheroids, dissociated, and exposed in vitro to varying amounts (range 100–500 MOI) of Fn. We found that Fn stably adheres to CSCs, likely by multiple interactions involving the tumor-associated Gal-GalNac disaccharide and the Fn-docking protein CEA-family cell adhesion molecule 1 (CEACAM-1), robustly expressed on CSCs. Importantly, Fn elicited innate immune responses in CSCs and triggered a growth factor-like, protein tyrosine phosphorylation cascade largely dependent on CEACAM-1 and culminating in the activation of p42/44 MAP kinase. Thus, the direct stimulation of CSCs by Fn may contribute to microbiota-driven colorectal carcinogenesis and represent a target for innovative therapies.

Original languageAmerican English
Article number1256
JournalBiomolecules
Volume12
Issue number9
DOIs
StatePublished - 7 Sep 2022

Bibliographical note

Publisher Copyright:
© 2022 by the authors.

Keywords

  • PTPase
  • bacterial adhesins
  • cancer stem cells
  • carcino-embryonic antigen cell adhesion molecule-1
  • colorectal cancer
  • fusobacterium nucleatum
  • microbiota
  • tumor microenvironment
  • tumor spheroids

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