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Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11–JAK/STAT3 pathway
Saara Ollila
1, 2, 3
Eva Domènech-Moreno
1, 2
Kaisa Laajanen
1, 2
Iris Pl Wong
1, 2
Sushil Tripathi
1, 2
Nalle Pentinmikko
4
Yajing Gao
1, 2
Yan Yan
1, 2
Elina Niemelä
1, 2
Timothy Wang
3
Benoit Viollet
5, *
Gustavo Leone
6
Pekka Katajisto
2, 4, 7
Kari Vaahtomeri
1
Tomi Mäkelä
1
*
Corresponding author
Saara Ollila 1, 2, 3
Author
Eva Domènech-Moreno 1, 2
Author
Kaisa Laajanen 1, 2
Author
Iris Pl Wong 1, 2
Author
Elina Niemelä 1, 2
Author
Timothy C Wang 3
Author
Benoit Viollet 5
Mail :
Correspondent author IdHAL : benoit-viollet ResearcherId : http://www.researcherid.com/rid/O-6927-2017 ORCID : https://orcid.org/0000-0002-0121-0224
Gustavo Leone 6
Author
1
Research Programs [Helsinki] (Haartmaninkatu 3 (P.O. Box 21)
FIN-00014 Helsinki, Finlande - Finland)
- Haartman Institute [Helsinki] (Haartmaninkatu 3 (P.O. Box 21)
FIN-00014. Helsinki, Finlande. - Finland)
- Faculty of Medecine [Helsinki] (P.O.Box 63
00014 Helsinki - Finland)
- University of Helsinki (Yliopistonkatu 4, 00100 Helsinki - Finland)
- Faculty of Medecine [Helsinki] (P.O.Box 63
00014 Helsinki - Finland)
2
NC - HiLIFE - Neuroscience Center (Finland)
- HiLIFE - Helsinki Institute of Life Science (P.O. Box 4
(Yliopistonkatu 3)
00014. Helsinki, Finlande. - Finland)
- University of Helsinki (Yliopistonkatu 4, 00100 Helsinki - Finland)
3
Department of Medicine - Division of Digestive and Liver Diseases [New York, NY, USA] (United States)
- CUIMC - Columbia University Irving Medical Center (Columbia University Medical Center 622 W 168th St, New York, NY 10032, États-Unis - United States)
- Irving Cancer Research Center [New York, NY, USA] (United States)
4
BI - HiLIFE - Institute of Biotechnology [Helsinki] (P.O.Box 56
00014. Helsinki, Finlande - Finland)
- HiLIFE - Helsinki Institute of Life Science (P.O. Box 4
(Yliopistonkatu 3)
00014. Helsinki, Finlande. - Finland)
- University of Helsinki (Yliopistonkatu 4, 00100 Helsinki - Finland)
5
EMD - [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (Institut Cochin- 22, rue Méchain- 75014 PARIS - )
- IC UM3 (UMR 8104 / U1016) - Institut Cochin (22 rue Méchain, 75014 Paris - France)
- UPD5 - Université Paris Descartes - Paris 5 : UM 3 (12, rue de l'École de Médecine - 75270 Paris cedex 06 - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U1016 (101, rue de Tolbiac, 75013 Paris - France)
- CNRS - Centre National de la Recherche Scientifique : UMR 8104 (France)
6
OSU - Ohio State University [Columbus] (Ohio State University Enarson Hall 154 W 12th Avenue Columbus, Ohio 43210 - United States)
7
Department of Biosciences and Nutrition [Stockholm, Sweden] (SE-141 83 Huddinge, Sweden - Sweden)
- Karolinska Institutet [Stockholm] (Solnavägen 1, 171 77 Solna Stockholm - Sweden)
Abstract : Germline mutations in the gene encoding tumor suppressor kinase LKB1 lead to gastrointestinal tumorigenesis in Peutz-Jeghers syndrome (PJS) patients and mouse models; however, the cell types and signaling pathways underlying tumor formation are unknown. Here, we demonstrated that mesenchymal progenitor- or stromal fibroblast-specific deletion of Lkb1 results in fully penetrant polyposis in mice. Lineage tracing and immunohistochemical analyses revealed clonal expansion of Lkb1-deficient myofibroblast-like cell foci in the tumor stroma. Loss of Lkb1 in stromal cells was associated with induction of an inflammatory program including IL-11 production and activation of the JAK/STAT3 pathway in tumor epithelia concomitant with proliferation. Importantly, treatment of LKB1-defcient mice with the JAK1/2 inhibitor ruxolitinib dramatically decreased polyposis. These data indicate that IL-11-mediated induction of JAK/STAT3 is critical in gastrointestinal tumorigenesis following Lkb1 mutations and suggest that targeting this pathway has therapeutic potential in Peutz-Jeghers syndrome.
Document type :
Journal articles
Complete list of metadatas
https://www.hal.inserm.fr/inserm-02349917
Contributor : Benoit Viollet <>
Submitted on : Tuesday, November 5, 2019 - 8:00:07 PM
Last modification on : Friday, March 27, 2020 - 2:47:48 AM
Document(s) archivé(s) le : Friday, February 7, 2020 - 5:23:53 AM
Contributor : Benoit Viollet <>
Submitted on : Tuesday, November 5, 2019 - 8:00:07 PM
Last modification on : Friday, March 27, 2020 - 2:47:48 AM
Document(s) archivé(s) le : Friday, February 7, 2020 - 5:23:53 AM
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Identifiers
- HAL Id : inserm-02349917, version 1
- DOI : 10.1172/JCI93597
- PUBMED : 29202476
Collections
CNRS | UNIV-PARIS5 | USPC
Citation
Saara Ollila, Eva Domènech-Moreno, Kaisa Laajanen, Iris Pl Wong, Sushil Tripathi, et al.. Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11–JAK/STAT3 pathway. Journal of Clinical Investigation, American Society for Clinical Investigation, 2018, 128 (1), pp.402-414. ⟨10.1172/JCI93597⟩. ⟨inserm-02349917⟩
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