Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within Interleukin-6 family cytokines
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 glandular epithelium ofKrasG12D;Pik3caH1047RorTrp53R172Hand/or ablation ofPtenorTrp53. We find thatKrasG12D;Pik3caH1047Ris sufficient to induce adenomas, and that lesions progress to carcinoma when also harboringPten-deletions. Additional challenge with eitherTrp53loss- 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 mutantTrp53-induced interleukin (IL)-11 to IL-6 dependency switch. Consistent with poorer survival of patients with high IL6 expression, we identify IL6/STAT3 signaling as a therapeutic vulnerability for TP53-mutant gastric cancer..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 29. Apr. Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Huber, Anne [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2024.04.22.590499 |
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| PPN (Katalog-ID): |
XBI043404014 |
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| 520 | |a 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 glandular epithelium ofKrasG12D;Pik3caH1047RorTrp53R172Hand/or ablation ofPtenorTrp53. We find thatKrasG12D;Pik3caH1047Ris sufficient to induce adenomas, and that lesions progress to carcinoma when also harboringPten-deletions. Additional challenge with eitherTrp53loss- 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 mutantTrp53-induced interleukin (IL)-11 to IL-6 dependency switch. Consistent with poorer survival of patients with high IL6 expression, we identify IL6/STAT3 signaling as a therapeutic vulnerability for TP53-mutant gastric cancer. | ||
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| 700 | 1 | |a Dijkstra, Christine |e verfasserin |4 aut | |
| 700 | 1 | |a Thiem, Stefan |e verfasserin |4 aut | |
| 700 | 1 | |a Huynh, Jennifer |e verfasserin |4 aut | |
| 700 | 1 | |a Poh, Ashleigh R. |e verfasserin |4 aut | |
| 700 | 1 | |a Konecnik, Joshua |e verfasserin |4 aut | |
| 700 | 1 | |a Jacob, Saumya P. |e verfasserin |4 aut | |
| 700 | 1 | |a Busuttil, Rita |e verfasserin |4 aut | |
| 700 | 1 | |a Liao, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Chisanga, David |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Alorro, Mariah G. |e verfasserin |4 aut | |
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| 700 | 1 | |a Eissmann, Moritz F. |e verfasserin |0 (orcid)0000-0002-2855-0616 |4 aut | |
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