Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines

Although aberrant activation of the KRAS and PI3K pathway alongside TP53 mutations account for frequent aberrations in human gastric cancers, neither the sequence nor the individual contributions of these mutations have been clarified. Here, we establish an allelic series of mice to afford condition...

Descripción completa

Detalles Bibliográficos
Autores: Huber, Anne, Allam, Amr H., Dijkstra, Christine, Thiem, Stefan, Huynh, Jennifer, Poh, Ashleigh R., Konecnik, Joshua, Jacob, Saumya P., Busuttil, Rita, Liao, Yang, Chisanga, David, Shi, Wei, Alorro, Mariah G., Forrow, Stephen, Tauriello, Daniele V. F., Batlle Gómez, Eduard, Boussioutas, Alex, Williams, David S., Buchert, Michael, Ernst, Matthias, Eissmann, Moritz F.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/216739
Acceso en línea:https://hdl.handle.net/2445/216739
Access Level:acceso abierto
Palabra clave:Càncer d'estómac
Interleucines
Citocines
Stomach cancer
Interleukins
Cytokines
id ES_3b1f9ea76b60d43569197a3a4f9dfb22
oai_identifier_str oai:diposit.ub.edu:2445/216739
network_acronym_str ES
network_name_str España
repository_id_str
spelling Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokinesHuber, AnneAllam, Amr H.Dijkstra, ChristineThiem, StefanHuynh, JenniferPoh, Ashleigh R.Konecnik, JoshuaJacob, Saumya P.Busuttil, RitaLiao, YangChisanga, DavidShi, WeiAlorro, Mariah G.Forrow, StephenTauriello, Daniele V. F.Batlle Gómez, EduardBoussioutas, AlexWilliams, David S.Buchert, MichaelErnst, MatthiasEissmann, Moritz F.Càncer d'estómacInterleucinesCitocinesStomach cancerInterleukinsCytokinesAlthough aberrant activation of the KRAS and PI3K pathway alongside TP53 mutations account for frequent aberrations in human gastric cancers, neither the sequence nor the individual contributions of these mutations have been clarified. Here, we establish an allelic series of mice to afford conditional expression in the glandular epithelium of KrasG12D;Pik3caH1047R G12D ; Pik3ca H1047R or Trp53R172H R172H and/or ablation of Pten or Trp53. . We find that KrasG12D;Pik3caH1047R G12D ; Pik3ca H1047R is sufficient to induce adenomas and that lesions progress to carcinoma when also harboring Pten deletions. An additional challenge with either Trp53 loss- or gain-of-function alleles further accelerated tumor progression and triggered metastatic disease. While tumor-intrinsic STAT3 signaling in response to gp130 family cytokines remained as a gatekeeper for all stages of tumor development, metastatic progression required a mutant Trp53-induced interleukin (IL)-11 to IL-6 dependency switch. Consistent with the poorer survival of patients with high IL-6 expression, we identify IL-6/STAT3 signaling as a therapeutic vulnerability for TP53-mutant gastric cancer.Elsevier2024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/216739Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1016/j.celrep.2024.114616Cell Reports, 2024, vol. 43, num. 8https://doi.org/10.1016/j.celrep.2024.114616cc-by (c) Huber, Anne et al., 2024http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2167392026-05-27T06:46:51Z
dc.title.none.fl_str_mv Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines
title Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines
spellingShingle Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines
Huber, Anne
Càncer d'estómac
Interleucines
Citocines
Stomach cancer
Interleukins
Cytokines
title_short Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines
title_full Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines
title_fullStr Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines
title_full_unstemmed Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines
title_sort Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines
dc.creator.none.fl_str_mv Huber, Anne
Allam, Amr H.
Dijkstra, Christine
Thiem, Stefan
Huynh, Jennifer
Poh, Ashleigh R.
Konecnik, Joshua
Jacob, Saumya P.
Busuttil, Rita
Liao, Yang
Chisanga, David
Shi, Wei
Alorro, Mariah G.
Forrow, Stephen
Tauriello, Daniele V. F.
Batlle Gómez, Eduard
Boussioutas, Alex
Williams, David S.
Buchert, Michael
Ernst, Matthias
Eissmann, Moritz F.
author Huber, Anne
author_facet Huber, Anne
Allam, Amr H.
Dijkstra, Christine
Thiem, Stefan
Huynh, Jennifer
Poh, Ashleigh R.
Konecnik, Joshua
Jacob, Saumya P.
Busuttil, Rita
Liao, Yang
Chisanga, David
Shi, Wei
Alorro, Mariah G.
Forrow, Stephen
Tauriello, Daniele V. F.
Batlle Gómez, Eduard
Boussioutas, Alex
Williams, David S.
Buchert, Michael
Ernst, Matthias
Eissmann, Moritz F.
author_role author
author2 Allam, Amr H.
Dijkstra, Christine
Thiem, Stefan
Huynh, Jennifer
Poh, Ashleigh R.
Konecnik, Joshua
Jacob, Saumya P.
Busuttil, Rita
Liao, Yang
Chisanga, David
Shi, Wei
Alorro, Mariah G.
Forrow, Stephen
Tauriello, Daniele V. F.
Batlle Gómez, Eduard
Boussioutas, Alex
Williams, David S.
Buchert, Michael
Ernst, Matthias
Eissmann, Moritz F.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Càncer d'estómac
Interleucines
Citocines
Stomach cancer
Interleukins
Cytokines
topic Càncer d'estómac
Interleucines
Citocines
Stomach cancer
Interleukins
Cytokines
description Although aberrant activation of the KRAS and PI3K pathway alongside TP53 mutations account for frequent aberrations in human gastric cancers, neither the sequence nor the individual contributions of these mutations have been clarified. Here, we establish an allelic series of mice to afford conditional expression in the glandular epithelium of KrasG12D;Pik3caH1047R G12D ; Pik3ca H1047R or Trp53R172H R172H and/or ablation of Pten or Trp53. . We find that KrasG12D;Pik3caH1047R G12D ; Pik3ca H1047R is sufficient to induce adenomas and that lesions progress to carcinoma when also harboring Pten deletions. An additional challenge with either Trp53 loss- or gain-of-function alleles further accelerated tumor progression and triggered metastatic disease. While tumor-intrinsic STAT3 signaling in response to gp130 family cytokines remained as a gatekeeper for all stages of tumor development, metastatic progression required a mutant Trp53-induced interleukin (IL)-11 to IL-6 dependency switch. Consistent with the poorer survival of patients with high IL-6 expression, we identify IL-6/STAT3 signaling as a therapeutic vulnerability for TP53-mutant gastric cancer.
publishDate 2024
dc.date.none.fl_str_mv 2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/216739
url https://hdl.handle.net/2445/216739
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.celrep.2024.114616
Cell Reports, 2024, vol. 43, num. 8
https://doi.org/10.1016/j.celrep.2024.114616
dc.rights.none.fl_str_mv cc-by (c) Huber, Anne et al., 2024
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Huber, Anne et al., 2024
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869406285785464832
score 15,812429

Similares en LA Referencia