Zeb2 drives invasive and microbiota-dependent colon carcinoma,Nature Cancer

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Zeb2 drives invasive and microbiota-dependent colon carcinoma
Nature Cancer ( IF 23.5 ) Pub Date : 2020-06-15 , DOI: 10.1038/s43018-020-0070-2
Karolina Slowicka _{1,

2,

3} , Ioanna Petta _{1,

3,

4} , Gillian Blancke _{1,

3,

4} , Esther Hoste _{1,

2} , Emilie Dumas _{1,

3,

4} , Mozes Sze _{1,

2} , Hanna Vikkula _{1,

2} , Enrico Radaelli _{5,

6} , Jody J Haigh _{7,

8} , Sven Jonckheere _{2,

9} , Joachim Taminau _{2,

9} , Niels Vandamme _{1,

2,

9} , Andy Wullaert _{1,

2,

3,

4} , Eugene Tulchinsky _{10,

11} , David Nittner _{12,

13} , Pieter Van Vlierberghe _{9,

14} , Gert De Hertogh ₁₅ , Pamela Baldin ₁₆ , Emre Etlioglu ₁₃ , Pratyaksha Wirapati ₁₇ , Louis Boon ₁₈ , Bart N Lambrecht _{1,

4} , Chris Callewaert ₁₉ , Sabine Tejpar ₁₃ , Steven Goossens _{2,

9,

14,

20} , Geert Berx _{2,

9} , Lars Vereecke _{1,

3,

4,

9} , Geert van Loo _{1,

2,

3,

9}

Affiliation

VIB Center for Inflammation Research, Ghent, Belgium.
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Ghent Gut Inflammation Group, Ghent University, Ghent, Belgium.
Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
KU Leuven Center for Human Genetics, Leuven, Belgium.
VIB Center for Brain & Disease Research, Leuven, Belgium.
Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, Manitoba, Canada.
Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
Cancer Research Institute Ghent, Ghent, Belgium.
University of Leicester, Leicester, UK.
Department of Biomedical Sciences, Nazarbayev University School of Medicine, Astana, Kazakhstan.
Histopathology Expertise Center, VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium.
Department of Oncology, University Hospital Leuven, KU Leuven, Leuven, Belgium.
Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
Department of Pathology, University Hospital Leuven, KU Leuven, Leuven, Belgium.
Department of Pathology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Bioceros, Utrecht, the Netherlands.
Center for Microbial Ecology and Technology, Ghent University, Ghent, Belgium.
Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.

Colorectal cancer (CRC) is highly prevalent in Western society, and increasing evidence indicates strong contributions of environmental factors and the intestinal microbiota to CRC initiation, progression and even metastasis. We have identified a synergistic inflammatory tumor-promoting mechanism through which the resident intestinal microbiota boosts invasive CRC development in an epithelial-to-mesenchymal transition-prone tissue environment. Intestinal epithelial cell (IEC)-specific transgenic expression of the epithelial-to-mesenchymal transition regulator Zeb2 in mice (Zeb2^IEC-Tg/+) leads to increased intestinal permeability, myeloid cell-driven inflammation and spontaneous invasive CRC development. Zeb2^IEC-Tg/+ mice develop a dysplastic colonic epithelium, which progresses to severely inflamed neoplastic lesions while the small intestinal epithelium remains normal. Zeb2^IEC-Tg/+ mice are characterized by intestinal dysbiosis, and microbiota depletion with broad-spectrum antibiotics or germ-free rederivation completely prevents cancer development. Zeb2^IEC-Tg/+ mice represent the first mouse model of spontaneous microbiota-dependent invasive CRC and will help us to better understand host–microbiome interactions driving CRC development in humans.

中文翻译：

Zeb2 驱动侵袭性和微生物群依赖性结肠癌

结直肠癌（CRC）在西方社会非常普遍，越来越多的证据表明环境因素和肠道微生物群对结直肠癌的发生、进展甚至转移有很大的贡献。我们已经确定了一种协同炎症性肿瘤促进机制，通过该机制，常驻肠道微生物群在易发生上皮-间质转化的组织环境中促进侵袭性 CRC 的发展。小鼠肠上皮细胞 (IEC) 特异性转基因表达上皮间质转化调节剂 Zeb2 (Zeb2 ^IEC-Tg/+ ) 导致肠道通透性增加、骨髓细胞驱动的炎症和自发侵袭性 CRC 发展。Zeb2 ^IEC-Tg/+小鼠形成发育不良的结肠上皮，其进展为严重发炎的肿瘤病变，而小肠上皮保持正常。Zeb2 ^IEC-Tg/+小鼠的特点是肠道菌群失调，而广谱抗生素或无菌再衍生的微生物群耗竭完全阻止了癌症的发展。Zeb2 ^IEC-Tg/+小鼠代表了自发性微生物群依赖性侵袭性 CRC 的第一个小鼠模型，将帮助我们更好地了解推动人类 CRC 发展的宿主-微生物组相互作用。

更新日期：2020-06-15

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