2026-04-14T07:01:19Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/2167392025-12-04T19:31:16Zcom_2072_1057col_2072_478908col_2072_478917

00925njm 22002777a 4500 dc Huber, Anne author Allam, Amr H. author Dijkstra, Christine author Thiem, Stefan author Huynh, Jennifer author Poh, Ashleigh R. author Konecnik, Joshua author Jacob, Saumya P. author Busuttil, Rita author Liao, Yang author Chisanga, David author Shi, Wei author Alorro, Mariah G. author Forrow, Stephen author Tauriello, Daniele V. F. author Batlle Gómez, Eduard author Boussioutas, Alex author Williams, David S. author Buchert, Michael author Ernst, Matthias author Eissmann, Moritz F. author 2024-11-26T10:04:01Z 2024-11-26T10:04:01Z 2024-08-27 2024-11-26T09:53:53Z 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. Càncer d'estómac Interleucines Citocines Stomach cancer Interleukins Cytokines Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines