Eva Domènech-Moreno, Wei-Wen Lim, Melissa G Montrose, Myriam Sévigny, Anders Brandt, Toni T Lemmetyinen, Emma W Viitala, Tomi P Mäkelä, Stuart A Cook, Saara Ollila
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Abstract
Peutz-Jeghers syndrome (PJS) is associated with early-onset gastrointestinal polyposis caused by hereditary inactivating pathogenic variants in the tumor suppressor gene STK11 (LKB1 ). Due to lack of prophylactic therapies, management of PJS polyps requires frequent surveillance. Interestingly, studies in mouse models have revealed that stromal cells drive the polyp formation, but detailed understanding of the cell types and interactions involved has been lacking. Using single-cell RNA sequencing of PJS mouse model polyps, we here identify a polyp-enriched crypt top fibroblast (pCTF) cluster characterized by a transcriptional signature also enriched in PJS patient polyps. The pCTF signature was also noted in primary fibroblasts in vitro following acute STK11 loss. Targeted deletion of Stk11 in crypt top fibroblasts using Foxl1 -Cre led to upregulation of the pCTF signature genes and later to polyposis. pCTFs displayed similarity to inflammation-associated fibroblasts, and polyposis was exacerbated by inflammation. Cell–cell communication analysis identified interleukin 11 (IL-11) as a potential pCTF inducer, and consistent with this, IL-11 was required for fibroblast reprogramming toward pCTFs following STK11 loss. Importantly, a neutralizing IL-11 antibody efficiently reduced polyp formation in a PJS model indicating a key, targetable role for IL-11 in polyp development. Together the results characterize pCTFs as a PJS polyp-enriched fibroblast subset and identify IL-11 as a key mediator of fibroblast reprogramming and a potential therapeutic target in PJS. © 2025 The Pathological Society of Great Britain and Ireland.
在息肉富集的成纤维细胞亚群中表达的白介素-11是Peutz-Jeghers综合征的潜在治疗靶点。
Peutz-Jeghers综合征(PJS)与肿瘤抑制基因STK11 (LKB1)的遗传失活致病性变异引起的早发性胃肠道息肉病有关。由于缺乏预防性治疗,PJS息肉的治疗需要经常监测。有趣的是,对小鼠模型的研究表明基质细胞驱动息肉的形成,但对细胞类型和所涉及的相互作用的详细了解一直缺乏。利用PJS小鼠模型息肉的单细胞RNA测序,我们在这里鉴定了一个富含息肉的隐窝顶部成纤维细胞(pCTF)簇,其转录特征也在PJS患者息肉中富集。急性STK11缺失后,在体外原代成纤维细胞中也发现了pCTF特征。使用Foxl1-Cre在隐窝顶成纤维细胞中靶向删除Stk11导致pCTF特征基因上调,随后导致息肉病。pctf与炎症相关成纤维细胞相似,炎症加重息肉病。细胞间通讯分析发现,白细胞介素11 (IL-11)是一种潜在的pCTF诱导剂,与此一致的是,在STK11缺失后,成纤维细胞向pCTF重编程需要IL-11。重要的是,在PJS模型中,一种中和的IL-11抗体有效地减少了息肉的形成,这表明IL-11在息肉发育中具有关键的靶向作用。总之,这些结果将pctf描述为PJS息肉富集的成纤维细胞亚群,并确定IL-11是成纤维细胞重编程的关键介质和PJS的潜在治疗靶点。©2025英国和爱尔兰病理学会。
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