| Title: |
Interleukin-11 expressed in the polyp-enriched fibroblast subset is a potential therapeutic target in Peutz-Jeghers syndrome |
| Authors: |
Domenech-Moreno, Eva; Lim, Wei-Wen; Montrose, Melissa G.; Sevigny, Myriam; Brandt, Anders; Lemmetyinen, Toni T.; Viitala, Emma W.; Mäkelä, Tomi P.; Cook, Stuart A.; Ollila, Saara |
| Contributors: |
Helsinki Institute of Life Science HiLIFE; University of Helsinki; Digital Precision Cancer Medicine (iCAN); Department of Molecular and Integrative Biosciences; CAN-PRO - Translational Cancer Medicine Program; Research Programs Unit; Department of Medicine; HUS Group; Department of Biochemistry and Developmental Biology; Mäkelä Lab; Faculty of Biological and Environmental Sciences |
| Publisher Information: |
John Wiley and Sons Ltd |
| Publication Year: |
2026 |
| Collection: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| Subject Terms: |
Lkb1; Peutz-Jeghers syndrome; Stk11; Interleukin-11; Polyposis; single-cell RNA sequencing; Therapy; Cancers |
| Description: |
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. (c) 2025 The Pathological Society of Great Britain and Ireland. ; Peer reviewed |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
Mouse experiments were carried out with the support of HiLIFE Laboratory Animal Centre Core Facility, University of Helsinki, Finland. The 3' RNA sequencing analysis was conducted at the Biomedicum Functional Genomics Unit, located at the Helsinki Institute of Life Science and Biocenter, Finland, affiliated with the University of Helsinki. The gRNA constructs were generated by the Genome Biology Unit supported by HiLIFE and the Faculty of Medicine, University of Helsinki, and Biocenter Finland. LentiCRISPR v2 was a gift from Feng Zhang (Addgene plasmid no. 52961). Images were generated using 3DHISTECH Pannoramic 250 FLASH III digital slide scanner at the Genome Biology Unit supported by HiLIFE and the Faculty of Medicine, University of Helsinki, and Biocenter Finland. The flow cytometry was performed at the HiLIFE Flow Cytometry Unit, University of Helsinki. Roni Liimatta is thanked for help in gRNA design and Reeta Huhtala and Riikka Saikkonen for technical assistance. We are grateful to Chen Xie and Daryl Yeong for their technical assistance rendered to for colony maintenance, antibody treatments, and tissue harvests of the Stk11+/- mice performed at National Heart Centre Singapore, Singapore. This study was supported by grants from Academy of Finland (grants 320145 to SO and 1320185 to TPM), University of Helsinki Research Foundation, Finnish Cancer Foundation, Biomedicum Helsinki-saatio, and the K. Albin Johanssons Stiftelse (to EDM). SAC is supported by the Ministry of Health (MOH) National Medical Research Council (NMRC): Singapore Translational Research Investigator Award (STaR21nov-003), Clinician Scientist Individual Research Grant (CIRG18nov-0007), GohCardiovascular Research Award (Duke-NUS-GCR/2015/0014), and the Tanoto Foundation. W-WL is supported by the Agency for Science, Technology and Research (A*STAR) award (A2084c0157).; https://hdl.handle.net/10138/628018; 105000324071; 001441773000001 |
| Availability: |
https://hdl.handle.net/10138/628018 |
| Rights: |
cc_by ; info:eu-repo/semantics/openAccess ; openAccess |
| Accession Number: |
edsbas.14058C4C |
| Database: |
BASE |