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...

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Detalhes 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.
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/216739
Acesso em linha:https://hdl.handle.net/2445/216739
Access Level:acceso abierto
Palavra-chave:Càncer d'estómac
Interleucines
Citocines
Stomach cancer
Interleukins
Cytokines
Descrição
Resumo: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.

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