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

doi:10.1016/j.celrep.2024.114616

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 ErnstMoritz F. Eissmann

Gastroenterology

Research output: Contribution to journal › Article › Research › peer-review

3 Citations (Scopus)

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 Kras^G12D;Pik3ca^H1047R or Trp53^R172H and/or ablation of Pten or Trp53. We find that Kras^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.

Original language	English
Article number	114616
Number of pages	21
Journal	Cell Reports
Volume	43
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2024.114616
Publication status	Published - 27 Aug 2024

Keywords

animal model
CP: Cancer
cytokine signaling
gastric carcinoma
interleukin-11
interleukin-6
metastasis
organoids
STAT3
TP53
WNT

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2024.114616Licence: CC BY

Cite this

Huber, A., Allam, A. H., Dijkstra, C., Thiem, S., Huynh, J., Poh, A. R., Konecnik, J., Jacob, S. P., Busuttil, R., Liao, Y., Chisanga, D., Shi, W., Alorro, M. G., Forrow, S., Tauriello, D. V. F., Batlle, E., Boussioutas, A., Williams, D. S., Buchert, M., ... Eissmann, M. F. (2024). Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines. Cell Reports, 43(8), Article 114616. https://doi.org/10.1016/j.celrep.2024.114616

@article{6fb40a922aab46f39c805dc7f48ac0c1,

title = "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 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.",

keywords = "animal model, CP: Cancer, cytokine signaling, gastric carcinoma, interleukin-11, interleukin-6, metastasis, organoids, STAT3, TP53, WNT",

author = "Anne Huber and Allam, {Amr H.} and Christine Dijkstra and Stefan Thiem and Jennifer Huynh and Poh, {Ashleigh R.} and Joshua Konecnik and Jacob, {Saumya P.} and Rita Busuttil and Yang Liao and David Chisanga and Wei Shi and Alorro, {Mariah G.} and Stephen Forrow and Tauriello, {Daniele V.F.} and Eduard Batlle and Alex Boussioutas and Williams, {David S.} and Michael Buchert and Matthias Ernst and Eissmann, {Moritz F.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = aug,

day = "27",

doi = "10.1016/j.celrep.2024.114616",

language = "English",

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Huber, A, Allam, AH, Dijkstra, C, Thiem, S, Huynh, J, Poh, AR, Konecnik, J, Jacob, SP, Busuttil, R, Liao, Y, Chisanga, D , Shi, W, Alorro, MG, Forrow, S, Tauriello, DVF, Batlle, E, Boussioutas, A, Williams, DS, Buchert, M, Ernst, M & Eissmann, MF 2024, 'Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines', Cell Reports, vol. 43, no. 8, 114616. https://doi.org/10.1016/j.celrep.2024.114616

TY - JOUR

T1 - Mutant TP53 switches therapeutic vulnerability during gastric cancer progression within interleukin-6 family cytokines

AU - Huber, Anne

AU - Allam, Amr H.

AU - Dijkstra, Christine

AU - Thiem, Stefan

AU - Huynh, Jennifer

AU - Poh, Ashleigh R.

AU - Konecnik, Joshua

AU - Jacob, Saumya P.

AU - Busuttil, Rita

AU - Liao, Yang

AU - Chisanga, David

AU - Shi, Wei

AU - Alorro, Mariah G.

AU - Forrow, Stephen

AU - Tauriello, Daniele V.F.

AU - Batlle, Eduard

AU - Boussioutas, Alex

AU - Williams, David S.

AU - Buchert, Michael

AU - Ernst, Matthias

AU - Eissmann, Moritz F.

PY - 2024/8/27

Y1 - 2024/8/27

N2 - 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.

AB - 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.

KW - animal model

KW - CP: Cancer

KW - cytokine signaling

KW - gastric carcinoma

KW - interleukin-11

KW - interleukin-6

KW - metastasis

KW - organoids

KW - STAT3

KW - TP53

KW - WNT

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U2 - 10.1016/j.celrep.2024.114616

DO - 10.1016/j.celrep.2024.114616

M3 - Article

C2 - 39128004

AN - SCOPUS:85200800431

SN - 2639-1856

VL - 43

JO - Cell Reports

JF - Cell Reports

IS - 8

M1 - 114616

ER -

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

Abstract

Keywords

UN SDGs

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Other files and links

Dissecting the role of group 2 innate lymphoid cells in gastric cancer

Cite this

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Projects

Dissecting the role of group 2 innate lymphoid cells in gastric cancer

Cite this