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Huber et al_Cell Reports_2024.pdf (7 MB)

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2024-08-27

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cc-by (c) Huber, Anne et al., 2024
Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/216739

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

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https://doi.org/10.1016/j.celrep.2024.114616

Abstract

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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Càncer d'estómac, Interleucines, Citocines

Subject (English)

Stomach cancer, Interleukins, Cytokines

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Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona))

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HUBER, Anne, et al. Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines. Cell Reports. 2024. Vol. 43, num. 8. ISSN 2211-1247. [consulted: 10 of August of 2026]. Available at: https://hdl.handle.net/2445/216739

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