Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines
Anne Huber,
Amr H. Allam,
Christine Dijkstra,
Stefan Thiem,
Jennifer Huynh,
Ashleigh R. Poh,
Joshua Konecnik,
Saumya P. Jacob,
Rita Busuttil,
Yang Liao,
David Chisanga,
Wei Shi,
Mariah G. Alorro,
Stephen Forrow,
Daniele V.F. Tauriello,
Eduard Batlle,
Alex Boussioutas,
David S. Williams,
Michael Buchert,
Matthias Ernst,
Moritz F. Eissmann
Affiliations
Anne Huber
Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
Amr H. Allam
Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
Christine Dijkstra
Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
Stefan Thiem
Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
Jennifer Huynh
Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
Ashleigh R. Poh
Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
Joshua Konecnik
Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
Saumya P. Jacob
Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
Rita Busuttil
Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; Department of Gastroenterology, The Alfred Hospital, Melbourne, VIC 3004, Australia
Yang Liao
Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
David Chisanga
Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
Wei Shi
Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
Mariah G. Alorro
Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
Stephen Forrow
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain
Daniele V.F. Tauriello
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain
Eduard Batlle
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
Alex Boussioutas
Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; Department of Gastroenterology, The Alfred Hospital, Melbourne, VIC 3004, Australia
David S. Williams
Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia; Department of Anatomical Pathology, Austin Health, Heidelberg, VIC 3084, Australia
Michael Buchert
Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia
Matthias Ernst
Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia; Corresponding author
Moritz F. Eissmann
Olivia Newton-John Cancer Research Institute and School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia; Corresponding author
Summary: 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 or Trp53R172H and/or ablation of Pten or Trp53. We find that KrasG12D;Pik3caH1047R 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.
