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 conditional expression in the glandular epithelium of Kras<sup>G12D</sup>;Pik3ca<sup>H1047R</sup> or Trp53<sup>R172H</sup> and/or ablation of Pten or Trp53. We find that Kras<sup>G12D</sup>;Pik3ca<sup>H1047R</sup> 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.
Authors
- Jennifer Huynh (ORCID: https://orcid.org/0000-0002-2638-8352)
- Yang Liao
- Ashleigh R. Poh (ORCID: https://orcid.org/0000-0001-8375-4753)
- Amr H. Allam (ORCID: https://orcid.org/0000-0002-8743-3639)
- Moritz F. Eissmann (ORCID: https://orcid.org/0000-0002-2855-0616)
- David Chisanga
- Michael Büchert (ORCID: https://orcid.org/0000-0003-2672-0148)
- Daniele V. F. Tauriello (ORCID: https://orcid.org/0000-0003-1522-3496)
- Saumya P. Jacob
- Stephen Forrow
- Rita A. Busuttil (ORCID: https://orcid.org/0000-0002-2261-3495)
- Matthias Ernst (ORCID: https://orcid.org/0000-0002-6399-1177)
- Wei Shi (ORCID: https://orcid.org/0000-0003-1182-7735)
- Stefan Thiem
- David S. Williams (ORCID: https://orcid.org/0000-0002-7758-3932)
- Eduard Batlle (ORCID: https://orcid.org/0000-0003-2422-0326)
- Mariah Alorro (ORCID: https://orcid.org/0000-0002-2098-2801)
- Alex Boussioutas (ORCID: https://orcid.org/0000-0002-8109-6897)
- Joshua Konecnik
- Anne Huber
- Christine D. Dijkstra
Institutions
- Institució Catalana de Recerca i Estudis Avançats (ES)
- La Trobe University (AU)
- The Alfred Hospital (AU)
- Monash Alfred Psychiatry Research centre (AU)
- Institute for Research in Biomedicine (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Olivia Newton-John Cancer Wellness & Research Centre (AU)
- Austin Health (AU)
- Monash University (AU)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-08-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114616
- Citations
- 13
- Primary Topic
- Cytokine Signaling Pathways and Interactions
- Type
- article
- Field-Weighted Citation Impact
- 3.67