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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Agrawal, D; Cisarova, K; Vosberg, S; Allmendinger, F; Munkhbaatar, E; Dandachi, N; Fernandez, Hernandez, FJ; Tonietto, M; Jäger, V; Anton, M; Keller, EC; Jesinghaus, M; Meinhardt, AL; Haefner, V; Stoeger, T; Steiger, K; McGranahan, N; Dengler, MA; Wahida, A; Jost, PJ.
Aberrant methylation limits antitumoral inflammation in lung adenocarcinoma by restricting RIPK3 expression.
Sci Adv. 2026; 12(4):eadz9227 Doi: 10.1126/sciadv.adz9227
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Führende Autor*innen der Med Uni Graz

Jost Philipp

Vizar Cisarova Katarina

Co-Autor*innen der Med Uni Graz

Dandachi Nadia

Dengler Michael

Fernandez Hernandez Francisco Jose

Jäger Vanessa

Tonietto Marta

Vosberg Sebastian

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Abstract:

Evasion of programmed cell death is a critical hallmark of cancer. However, the contribution of inflammatory forms of cell death in lung carcinogenesis and their effects on the composition of the tumor-immune microenvironment remain unclear. Our multi-omics analyses of samples from patients with primary lung adenocarcinoma revealed that necrosome signaling is repressed because of reduced expression of receptor-interacting protein kinase 3 (RIPK3). Distinct methylation signatures, both in the RIPK3 promoter and nonpromoter regions, correlated with lower transcription levels of RIPK3. This resulted in limited expression of inflammatory genes, advanced histologic features, reduced immune cell invasion, and decreased patient survival. Mechanistically, we confirmed the tumor-suppressive role of necrosome signaling through the genetic deletion of Ripk3 in two independent, clinically relevant mouse models of lung adenocarcinoma. Functionally, RIPK3 shaped a diverse immune environment by promoting the invasion of innate and adaptive immune cells in patient samples and experimental mice. Thus, RIPK3-mediated inflammatory signaling enhances a diverse immune microenvironment and hinders progression in lung adenocarcinoma.

Find related publications in this database (using NLM MeSH Indexing)

Receptor-Interacting Protein Serine-Threonine Kinases - genetics, metabolism

Adenocarcinoma of Lung - genetics, pathology, metabolism, immunology

Animals - administration & dosage

Humans - administration & dosage

Mice - administration & dosage

Lung Neoplasms - genetics, pathology, metabolism, immunology

Inflammation - genetics, pathology, metabolism

DNA Methylation - administration & dosage

Tumor Microenvironment - genetics, immunology

Gene Expression Regulation, Neoplastic - administration & dosage

Signal Transduction - administration & dosage

Disease Models, Animal - administration & dosage

Cell Line, Tumor - administration & dosage

Promoter Regions, Genetic - administration & dosage

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