Biology subjects

Schafmayer, C.

Publications and source records attributed to Schafmayer, C..

3 recordsLinked to original sources

bioRxiv2023

ATF6 activation alters colonic lipid metabolism causing tumor-associated microbial adaptation

Endoplasmic reticulum unfolded protein responses (UPRER) contribute to cancer development and the activating transcription factor 6 (ATF6) is involved in microbiota-dependent tumorigenesis. Here, we substantiate the clinical relevance of ATF6 in early-onset and late colorectal cancer patient cohorts. Transcriptional analysis in intestinal epithelial cells (IEC) of ATF6 transgenic mice (nATF6IEC) identified bacteria-specific changes in cellular metabolism enriched for fatty acid biosynthesis. Untargeted metabolomics and isotype-labeling confirmed ATF6-related enrichment of long chain fatty acids in colonic tissue of patients, mice and organoid cultures. FASN inhibition and microbiota transfer in germ-free nATF6IEC mice confirmed the causal involvement of ATF6-induced lipid alterations in tumorigenesis. The selective expansion of tumor-relevant microbial taxa was mechanistically linked to long chain fatty acid exposure, using bioorthogonal non-canonical amino acid tagging (BONCAT) and growth analysis of Desulfovibrio isolates. We postulate chronic ATF6 signaling in the epithelium to select for tumor-promoting microbiota by altering lipid metabolism. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/565267v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@be3756org.highwire.dtl.DTLVardef@231da4org.highwire.dtl.DTLVardef@16f3aaeorg.highwire.dtl.DTLVardef@1758fe3_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Chronic ATF6 signaling in the colonic epithelium alters lipid metabolism to select a tumor-promoting microbiota C_FIG O_LIBiallelic expression of activated ATF6 (p50 nuclear fragment) in intestinal epithelial cells (nATF6IEC) induces spontaneous colon tumors in SPF but not GF mice C_LIO_LIMechanistically, biallelic SPF nATF6IEC mice alter colonic lipid metabolism, including the upregulation of LCFAs and Fasn C_LIO_LIInhibition of FASN prevents colon tumor formation in mice, and reduces the tumor-promoting potential of the intestinal microbiota (FMT) C_LIO_LIExposure of fl/fl control mouse microbiota to LCFAs ex vivo translationally activates tumor-associated bacteria, including Desulfovibrio fairfieldensis C_LIO_LIHuman CRC patients show ATF6 upregulation, FASN co-occurrence and increased LCFAs in T tissue C_LIO_LIATF6 activity links with CRC-associated microbiota in patients, including Desulfovibrio C_LI Created with BioRender.com nATF6: activated activating transcription factor 6; LCFA: long-chain fatty acids; SAFA: saturated fatty acids; Fasn: fatty acid synthase; C75 i.p.: intraperitoneal injection of the Fasn inhibitor C75.

cancer biology↗

bioRxiv2019

3D spatially-resolved geometrical and functional models of human liver tissue reveal new aspects of NAFLD progression

Early disease diagnosis is key for the effective treatment of diseases. It relies on the identification of biomarkers and morphological inspection of organs and tissues. Histopathological analysis of human biopsies is the gold standard to diagnose tissue alterations. However, this approach has low resolution and overlooks 3D structural changes that are consequence of functional alterations. Here, we applied multiphoton imaging, 3D digital reconstructions and computational simulations to generate spatially-resolved geometrical and functional models of human liver tissue at different stages of non-alcoholic fatty liver disease (NAFLD). We identified a set of new morphometric cellular parameters correlated with disease progression. Moreover, we found profound topological defects in the 3D bile canaliculi (BC) network. Personalized biliary fluid dynamic simulations predicted an increased pericentral biliary pressure and zonated cholestasis, consistent with elevated cholestatic biomarkers in patients sera. Our spatially-resolved models of human liver tissue can contribute to high-definition medicine by identifying quantitative multi-parametric cellular and tissue signatures to define disease progression and provide new insights into NAFLD pathophysiology.

pathology↗

bioRxiv2018

Common variants in ABCG8 and TRAF3 genes confer risk for gallstone disease and gallbladder cancer in admixed Latinos with Mapuche Native American ancestry

BackgroundLatin Americans and Chilean Amerindians have the highest prevalence of cholesterol gallstone disease (GSD) and gallbladder cancer (GBC) in the world. A handful of loci have been associated with GSD in populations of predominantly European ancestry, however they only explain a small portion of the population-attributable risk of the disease.\n\nMethodsWe performed a genome-wide association study (GWAS) for GSD in 1,095 admixed Latinos with Mapuche Native American Ancestry, followed by a replication analysis of 10 candidate single nucleotide polymorphisms (SNPs) with suggestive genome-wide significance (P<1x10-5) in 1,643 individuals. Disease status was assessed by cholecystectomy or abdominal ultrasonography. Logistic regression analyses were adjusted for age, sex, BMI, Type 2 Diabetes and Amerindian ancestry. Associated variants were further examined in two large GSD European populations and in a Chilean gallbladder cancer (GBC) cohort. We determined the expression levels of a novel GSD-candidate gene in normal and GSD-tissue samples.\n\nResultsWe consistently replicated the ABCG8 gene (rs11887534; P=3.24x10-8, OR=1.74) associated with GSD in admixed Latinos and identified a novel candidate signal within the TRAF3 gene on chromosome 14 (rs12882491; P=1.11x10-7, OR=1.40). ABCG8 and TRAF3 variants also conferred risk to GBC. Gene expression analyses indicated that TRAF3 levels were significantly decreased in the gallbladder (P=0.015) and the duodenal mucosa (P=0.001) of affected GSD individuals compared to healthy controls.\n\nConclusionsWe confirmed ABCG8 and identified TRAF3 both associated with GSD and GBC in admixed Latinos. Decreased TRAF3 expression levels could enhance gallbladder inflammation as is observed in GSD and GSD-associated GBC.

genetics↗