title: Induction of intestinal stemness and tumorigenicity by aberrant internalization of commensal non-pathogenic E. coli.
abstract: Commensal Escherichia coli has been identified as a major protagonist of microbe-induced colorectal oncogenesis. Its tumour-promoting attribute is linked to the expression of DNA-damaging genotoxins. Using a constitutively invasive variant of non-pathogenic E. coli, we demonstrate that chronic presence of internalized E. coli leads to enhanced oncogenicity in colon cancer cells. Instead of genomic damage, the tumorigenic effect is mediated through an expansion of the cancer stem cell (CSC) population, likely through dedifferentiation of lineage-committed intestinal epithelial cells. Stemness-linked intestinal tumorigenicity is directly correlated to absence of microbial virulence factor expression and is specific for intestinal cells. The enriched CSC fraction remains stable in the absence of the instigating bacteria and can foster stemness traits in unexposed cells through secreted factors. Mechanistically, aberrant host invasion leads to realignment of multiple host signal transduction cascades, notably mutually re-enforcing NF-κB and β-catenin activation, through reciprocal modulation of microbe sensing pathways Nod1/Rip2 and TLR/MyD88. The expanded tumorigenic CSC population is marked by enhanced malignancy traits, long-term self-renewal capacity and robust tumorigenic ability, both in vitro and in vivo. Our study shows that microbe-induced oncogenicity is not a strict correlate of commensal virulence and can be invoked by even non-pathogenic E. coli by engendering tumorigenic stemness in host cells.
authors.affiliation: Jamia Hamdard-Institute of Molecular Medicine, Jamia Hamdard, New Delhi 110062, India.|Department of Medical Elementology and Toxicology, Jamia Hamdard, New Delhi 110062, India.
authors.forename: Upasana
authors.initials: U
authors.lastname: Sahu
authors.affiliation: Jamia Hamdard-Institute of Molecular Medicine, Jamia Hamdard, New Delhi 110062, India.
authors.forename: Arnab
authors.initials: A
authors.lastname: Choudhury
authors.affiliation: Department of Medical Elementology and Toxicology, Jamia Hamdard, New Delhi 110062, India.
authors.forename: Suhel
authors.initials: S
authors.lastname: Parvez
authors.affiliation: Institute of Liver and Biliary Sciences, New Delhi 110070, India.
authors.forename: Subhrajit
authors.initials: S
authors.lastname: Biswas
authors.affiliation: Jamia Hamdard-Institute of Molecular Medicine, Jamia Hamdard, New Delhi 110062, India.
authors.forename: Sudeshna
authors.initials: S
authors.lastname: Kar
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003106:Colon / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D004926:Escherichia coli / Q000472:pathogenicity*; D045325:HCT116 Cells; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000382:microbiology* / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology*; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
chemical_list: D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D053474:Nod1 Signaling Adaptor Protein; D051176:beta Catenin; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2