Houle, L. | Search bioRxiv

bioRxiv2025

Colibactin-producing E. coli promote carcinogenesis of gastroesophageal adenocarcinoma and simultaneously induce autophagy and differentiation

Background & AimsGastroesophageal adenocarcinoma (GEAC) is a malignancy of the gastroesophageal junction (GEJ) and is associated with reflux of gastroduodenal contents and Barretts Esophagus (BE). A shift towards gram-negative bacteria in the microbiota of the GEJ additionally promotes inflammation and likely carcinogenesis. Enterobacteriaceae are enriched in advanced stages of GEAC development, and members of this family can produce colibactin, a genotoxin implicated in DNA damage and tumor progression. We aimed to validate these observations and investigate the effect of E. coli with or without colibactin production on GEAC-carcinogenesis. MethodsBacteria were profiled in human biopsies with imaging and 16S rRNA gene sequencing. Organoids of our L2-IL1B mouse model of GEAC were exposed to E. coli with colibactin (CoPEC) and without colibactin production (noCoPEC) via organoid microinjection. The phenotypic and transcriptomic changes in the organoids after the coculture with E. coli were evaluated via histology and single-cell RNA sequencing. ResultsIn human specimens, we observed an infiltration of bacteria in GEJ-tissue upon tumor formation and detected Enterobacteriaceae in one third of BE-patients. CoPEC-injected organoids exhibited high rates of proliferation and DNA damage, and an upregulation of cancer-associated genes and pathways. Furthermore, genes and pathways associated with immune activation, defense mechanisms, metabolic reprogramming, autophagy and differentiation were upregulated in CoPEC-injected organoids. ConclusionIn addition to the enrichment of Enterobacteriaceae in the GEJ-tissue of patients at late stages of GEAC, we show that the exposure of colibactin-producing E. coli to murine BE-organoids promotes genetic instability and proliferation, and the activation of cancer-associated pathways, while also activating autophagy and enhancing intercellular homeostasis. This indicates that colibactin-producing E. coli have a dual effect on early stages of GEAC-carcinogenesis. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/687579v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1281a14org.highwire.dtl.DTLVardef@1c83c91org.highwire.dtl.DTLVardef@10088d2org.highwire.dtl.DTLVardef@1698a2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Morphometric Analysis of Lungfish Endocasts Elucidates Early Dipnoan Palaeoneurological Evolution

Lungfish (Dipnoi) are lobe-finned fish (Sarcopterygii) that have persisted for over 400 million years from the Devonian Period to present day. They are the extant sister group to tetrapods and thus have the ability to provide unique insight into the condition of the earliest tetrapods as well as their own evolutionary history. The evolution of their dermal skull and dentition is relatively well understood, but this is not the case for the central nervous system. While the brain itself has very poor preservation potential and is not currently known in any fossil lungfish, substantial indirect information about it and associated structures such as the inner ears can be obtained from the cranial endocast. However, before the recent development of X-ray tomography as a palaeontological tool, these endocasts could not be studied non-destructively, and few detailed studies were undertaken. Here we describe and illustrate the endocasts of six Palaeozoic lungfishes (Iowadipterus halli, Gogodipterus paddyensis, Pillararhynchus longi, Griphognathus whitei, Orlovichthys limnatis, and Rhinodipterus ulrichi) from tomographic scans. We combine these with six previously described lungfish endocasts (4 fossil and 2 recent taxa), also based on tomographic studies, into a 12-taxon data set for multivariate morphometric analysis using 17 variables. We find that the olfactory region appears to be more highly plastic than the hindbrain, and undergoes significant elongation in several taxa. Further, while the semicircular canals covary as an integrated module, the utriculus and sacculus of the inner ear instead vary independently of each other. The functional and phylogenetic implications of our findings are discussed.

paleontology↗