Gastric cancer ranks the fifth most common and third leading cause of cancer‐related deaths worldwide. Alterations in the RTK/MAPK, WNT, cell adhesion, TP53, TGFβ, NOTCH, and NFκB signaling pathways could be identified as main oncogenic drivers. A combination of altered pathways can be associated with molecular subtypes of gastric cancer. In order to generate model systems to study the impact of different pathway alterations in a defined genetic background, we generated three murine organoid models: a RAS‐activated (KrasG12D, Tp53R172H), a WNT‐activated (Apcfl/fl, Tp53R172H), and a diffuse (Cdh1fl/fl, Apcfl/fl) model. These organoid models were morphologically and phenotypically diverse, differed in proteome expression signatures and possessed individual drug sensitivities. A differential vulnerability to RTK/MAPK pathway interference based on the different mitogenic drivers and according to the level of dependence on the pathway could be uncovered. Furthermore, an association between RTK/MAPK pathway activity and susceptibility to HDAC inhibition was observed. This finding was further validated in patient‐derived organoids from gastric adenocarcinoma, thus identifying a novel treatment approach for RTK/MAPK pathway altered gastric cancer patients.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:90812 |
| Date | 06 June 2024 |
| Creators | Seidlitz, Therese, Schmäche, Tim, Garcίa, Fernando, Lee, Joon Ho, Qin, Nan, Kochall, Susan, Fohgrub, Juliane, Pauck, David, Rothe, Alexander, Koo, Bon‐Kyoung, Weitz, Jürgen, Remke, Marc, Muñoz, Javier, Stange, Daniel E. |
| Publisher | EMBO Press |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 1757-4684, e15705, 10.15252/emmm.202215705, info:eu-repo/grantAgreement/Europäische Union/H2020 | RIA/823839//European Proteomics Infrastructure Consortium providing Access/EPIC‐XS |
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