Journal Article

DKFZ-2026-02388

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Targeting Kras signalling in a Trp53/KrasG12D mouse and organoid model inhibits Barrett esophagus to gastroesophageal adenocarcinoma progression

Anand, A. ; Schoemig, L. R.DKFZ* ; Klaas, L. ; Glosch, A.-K. ; Proaño-Vasco, A. ; Borgmann, M. ; Khiat, M. ; Kuznetsov, A. ; Patel, V. B. ; Ritzkowski, C. ; Strangmann, J. ; Werner, T.DKFZ* ; Klar, R.DKFZ* ; Börries, M.DKFZ* ; Vieth, M. ; Müller, S. ; Rad, R.DKFZ* ; Flisikowski, K. ; Lange, S. ; Frank, K. J. ; Algül, H. ; Wang, T. ; Thimme, R. ; Quante, M.DKFZ*

2026
Springer Nature [London]

Abstract: The lack of experimental systems that faithfully model the genetic and phenotypic progression from Barrett’s esophagus (BE) to gastroesophageal adenocarcinoma (GEAC) has limited mechanistic discovery and preclinical testing. Here, we report a refined L2-IL-1B based mouse model engineered to capture two hallmark alterations of human GEAC: TP53 loss and elevated KRAS signalling driven by wildtype KRAS amplification, which we model in the L2-IL-1B mouse model by using oncogenic KrasG12D activation, since direct modelling of wildtype Kras amplification in vivo remains challenging. This combinatorial genetic approach accelerates malignant transformation and enables controlled, stage-resolved analysis of carcinogenesis at the gastroesophageal junction (GEJ). In parallel, murine KrasG12D driven and human KRAS wildtype amplified organoid systems recapitulate these in vivo phenotypes and provide a platform for functional interrogation of aberrant KRAS signalling, a frequent but understudied driver in GEAC. Using the human derived KRAS wildtype amplified organoids as treatment avatars in addition to the KrasG12D driven mouse model and its corresponding organoids, we demonstrate that KRAS dependent growth is selectively vulnerable to combined SHP2 + MEK1/2 or ERK1/2 inhibition, revealing a therapeutically targetable signalling axis. Together, these integrated in vivo and organoid platforms represent a technical advance for modelling BE progression, dissecting KRAS pathway biology, and evaluating targeted strategies for KRAS amplified GEAC.

Note: #DKTKZFB26#

---

Contributing Institute(s):

1. DKTK Koordinierungsstelle Freiburg (FR01)
2. DKTK Koordinierungsstelle München (MU01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

---

Database coverage:
; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF < 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

---