The ALPK1/TIFA/NF-κB axis links a bacterial carcinogen to R-loop-induced replication stress

Bauer, Michael; Naščáková, Zuzana; Mihai, Anca-Irina; Cheng, Phil F.; Levesque, Mitchell P.; Lampart, Simon; Hurwitz, Robert; Pfannkuch, Lennart; Dobrovolná, Jana; Jacobs, M.F.; Bartfeld, Sina; Dohlman, Anders B.; Shen, Xiling; Gall, Alevtina; Salama, Nina R.; Töpfer, Antonia; Weber, Achim; Meyer, Thomas F.; Janscak, Pavel; Müller, Anne

doi:10.1038/s41467-020-18857-z

Cited by 81 publications

(75 citation statements)

References 76 publications

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“…In particular, we found that the biosynthesis of ADP-heptose and the key gene hldE were significantly enriched in adenoma compared with control. ADP-heptose has been identified as a bacteria-linked carcinogen 36 and the key metabolic intermediate in the biosynthesis of LPS. It is a potent trigger for the activation of NF-κB signaling, which has been shown to promote tumorigenesis 37 and may be critical in perpetuating inflammation 38 .…”

Section: Discussionmentioning

confidence: 99%

Identification of microbial markers across populations in early detection of colorectal cancer

et al. 2021

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Associations between gut microbiota and colorectal cancer (CRC) have been widely investigated. However, the replicable markers for early-stage adenoma diagnosis across multiple populations remain elusive. Here, we perform an integrated analysis on 1056 public fecal samples, to identify adenoma-associated microbial markers for early detection of CRC. After adjusting for potential confounders, Random Forest classifiers are constructed with 11 markers to discriminate adenoma from control (area under the ROC curve (AUC) = 0.80), and 26 markers to discriminate adenoma from CRC (AUC = 0.89), respectively. Moreover, we validate the classifiers in two independent cohorts achieving AUCs of 0.78 and 0.84, respectively. Functional analysis reveals that the altered microbiome is characterized with increased ADP-l-glycero-beta-d-manno-heptose biosynthesis in adenoma and elevated menaquinone-10 biosynthesis in CRC. These findings are validated in a newly-collected cohort of 43 samples using quantitative real-time PCR. This work proves the validity of adenoma-specific markers across multi-populations, which would contribute to the early diagnosis and treatment of CRC.

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Section: Discussionmentioning

confidence: 99%

Identification of microbial markers across populations in early detection of colorectal cancer

et al. 2021

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“…Many studies focus on ways by which bacteria can contribute to colorectal cancer initiation and progression beyond the induction of mutations. Several non-intestinal organoid systems have been used to pinpoint bacterially driven activation of cancerassociated pathways, aberrant proliferation, and replication stress (Bauer et al, 2020;McCracken et al, 2014;Scanu et al, 2015). We anticipate that applying these methods to colorectal cancer organoids will reveal further causal relationships.…”

Section: Dna Damage Mutagenesis and Cancermentioning

confidence: 99%

Organoids and organs-on-chips: Insights into human gut-microbe interactions

Puschhof

Pleguezuelos-Manzano

Clevers

2021

Cell Host & Microbe

118

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The important and diverse roles of the gut microbiota in human health and disease are increasingly recognized. The difficulty of inferring causation from metagenomic microbiome sequencing studies and from mouse-human interspecies differences has prompted the development of sophisticated in vitro models of human gutmicrobe interactions. Here, we review recent advances in the co-culture of microbes with intestinal and colonic epithelia, comparing the rapidly developing fields of organoids and organs-on-chips with other standard models. We describe how specific individual processes by which microbes and epithelia interact can be recapitulated in vitro. Using examples of bacterial, viral, and parasitic infections, we highlight the advantages of each culture model and discuss current trends and future possibilities to build more complex co-cultures.

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“…The exact mechanism for the putative role of CagA in gastric carcinogenesis is still disputed [ 11 ], but it has been proposed that CagA produces an oncoprotein which could induce malignancy after being incorporated into a cell [ 12 ]. Alternatively, exposure of H. pylori carcinogen in vitro has been reported to induce DNA damage [ 13 ]. However, these two mechanisms presently lack support from convincing in vivo data.…”

Section: Gastric Cancermentioning

confidence: 99%

Gastritis, Gastric Polyps and Gastric Cancer

Fossmark

2021

IJMS

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Gastric cancer is still an important disease causing many deaths worldwide, although there has been a marked reduction in prevalence during the last few decades. The decline in gastric cancer prevalence is due to a reduction in Helicobacter pylori infection which has occurred for at least 50 years. The most probable mechanism for the carcinogenic effect of H. pylori is hypergastrinemia since H. pylori infected individuals do not have increased risk of gastric cancer before the development of oxyntic atrophy. When atrophy has developed, the carcinogenic process continues independent of H. pylori. Autoimmune gastritis also induces oxyntic atrophy leading to marked hypergastrinemia and development of ECL cell neoplasia as well as adenocarcinoma. Similarly, long-term treatment with efficient inhibitors of acid secretion like the proton pump inhibitors (PPIs) predisposes to ECL cell neoplasia of a different degree of malignancy. Contrasting the colon where most cancers develop from polyps, most polyps in the stomach have a low malignant potential. Nevertheless, gastric polyps may also give rise to cancer and have some risk factors and mechanisms in common with gastric cancer. In this overview the most common gastric polyps, i.e., hyperplastic polyps, adenomatous polyps and fundic gland polyps will be discussed with respect to etiology and particularly use of PPIs and relation to gastric carcinogenesis.

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The ALPK1/TIFA/NF-κB axis links a bacterial carcinogen to R-loop-induced replication stress

Cited by 81 publications

References 76 publications

Identification of microbial markers across populations in early detection of colorectal cancer

Identification of microbial markers across populations in early detection of colorectal cancer

Organoids and organs-on-chips: Insights into human gut-microbe interactions

Gastritis, Gastric Polyps and Gastric Cancer

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