Kövilein Janine, Sorbie Adam, Khaloian Sevana, Küntzel Vanessa, von Stern Miriam, Ahmed Mohamed, Jarosch Sebastian, Remke Marianne, Metwaly Amira, Reuss Elena M, Busch Dirk H, Allez Matthieu, Steiger Katja, Schraml Barbara, Coleman Olivia I, Haller Dirk
Chair of Nutrition and Immunology, School of Life Sciences, Technical University of Munich, Freising-Weihenstephan, Germany.
Biomedical Center, Faculty of Medicine, Ludwig Maximilian University of Munich, Institute for Cardiovascular Physiology and Pathophysiology, Planegg-Martinsried, Germany.
J Crohns Colitis. 2025 Jul 3;19(7). doi: 10.1093/ecco-jcc/jjaf102.
Chronic inflammation in inflammatory bowel disease (IBD) patients represents a risk factor for developing colitis-associated cancer (CAC). We previously linked the endoplasmic reticulum unfolded protein response (UPRER) signal transducer activating transcription factor 6 (ATF6) with spontaneous microbiota-dependent colonic adenoma development in mice expressing epithelial-specific activated ATF6 (nATF6IEC).
To investigate IBD-related risk factors in ATF6-mediated tumorigenesis, we crossed tumor-free monoallelic (tg/wt) nATF6IEC mice with interleukin-10 deficient mice (Il10-/-). We characterized our newly generated murine model under germ-free (GF) and specific pathogen-free (SPF) conditions, including tumor phenotype and immune cell characterizations, as well as complex human stool and minimal consortium colonizations.
IL-10 deficiency initiated tumor susceptibility, with 77% of 12-week tg/wt;Il10-/- mice developing colonic adenomas and invasive carcinomas in this novel CAC mouse model. Tumor formation correlated with mucosal immune cell infiltration, characterized by CD11b+ granulocytes and monocytes, and mucosa-associated dysbiosis. Colonization of germ-free nATF6IEC;Il10-/- mice with minimal biosynthetic consortia and IBD stool re-established CAC, confirming microbiota-dependent ATF6-driven tumorigenesis. Increased ATF6 expression in IBD patients during active disease highlights human relevance.
Our findings show that IBD susceptibility heightens the risk for ATF6-driven tumorigenesis.
炎症性肠病（IBD）患者的慢性炎症是发生结肠炎相关癌症（CAC）的一个风险因素。我们之前将内质网未折叠蛋白反应（UPRER）信号转导子激活转录因子6（ATF6）与表达上皮特异性激活型ATF6（nATF6IEC）的小鼠自发性微生物群依赖性结肠腺瘤的发生联系起来。
为了研究ATF6介导的肿瘤发生中与IBD相关的风险因素，我们将无肿瘤的单等位基因（tg/wt）nATF6IEC小鼠与白细胞介素10缺陷小鼠（Il10-/-）进行杂交。我们在无菌（GF）和无特定病原体（SPF）条件下对新生成的小鼠模型进行了表征，包括肿瘤表型和免疫细胞表征，以及复杂人类粪便和最小菌群定植。
IL-10缺乏引发了肿瘤易感性，在这个新的CAC小鼠模型中，12周龄的tg/wt;Il10-/-小鼠中有77%发生了结肠腺瘤和浸润性癌。肿瘤形成与黏膜免疫细胞浸润相关，其特征为CD11b+粒细胞和单核细胞，以及黏膜相关的生态失调。用最小生物合成菌群和IBD粪便对无菌nATF6IEC;Il10-/-小鼠进行定植可重建CAC，证实了微生物群依赖性ATF6驱动的肿瘤发生。IBD患者在疾病活动期ATF6表达增加凸显了其与人类的相关性。
我们的研究结果表明，IBD易感性增加了ATF6驱动的肿瘤发生风险。
