Biology subjects

Baumgarten, J.

Publications and source records attributed to Baumgarten, J..

3 recordsLinked to original sources

bioRxiv2026

Prolonged TGF-β locks NK cells in a dysfunctional state through persistent epigenetic remodeling of IRF, T-bet and EOMES binding sites

TGF-{beta} signaling is a major regulator of immune cell differentiation and function, yet whether prolonged signaling can durably imprint dysfunctional immune states independently of continued pathway engagement remains unclear. Here, we identify signal duration as a critical determinant of human natural killer (NK) cell fate: short-term TGF-{beta} exposure induces largely reversible transcriptional, chromatin and functional changes, whereas prolonged exposure establishes persistent effector dysfunction independent of continued signaling. Mechanistically, prolonged TGF-{beta} drives durable loss of chromatin accessibility at effector-associated regulatory elements, particularly those enriched for IRF, EOMES, and T-bet binding motifs, resulting in stable restriction of NK cell effector programs despite reversibility of active histone marks. In contrast, tissue residency-associated programs remain largely reversible, revealing that distinct NK cell fate programs differ fundamentally in their susceptibility to epigenetic fixation downstream of the same cytokine signal. SMAD4 CUT&RUN and knockout experiments further demonstrate that canonical TGF-{beta} signaling acts primarily through rewiring of upstream transcriptional regulatory networks rather than direct targeting of effector loci. Finally, NK cells from patients with hepatocellular carcinoma recapitulate key functional and epigenetic features of the persistent TGF-{beta}-associated state defined in vitro. Together, these findings identify signal duration as a critical determinant of TGF-{beta}-driven cell fate and demonstrate that prolonged TGF-{beta} exposure can induce epigenetically stabilized dysfunctional states that persist after signal withdrawal, with important implications for therapeutic strategies aimed at reversing chronic TGF-{beta}-mediated dysfunction.

immunology↗

bioRxiv2026

YAP/TEAD drives treatment-induced adaptive immunosuppression in EGFR-mutant lung cancer

Residual disease remains a major obstacle for achieving durable responses in patients treated with oncogene-targeted therapy. Drug-tolerant persister (DTP) cells emerging under treatment and persisting in residual tumors are considered to be the root of acquired resistance, yet their contribution to immune evasion in on-treatment tumors is poorly defined. Here, we show in the context of EGFR-mutant lung cancer that DTP cells actively contribute to the formation of an immunosuppressive tumor microenvironment during EGFR tyrosine kinase inhibitor (TKI) therapy. In syngeneic mouse models and in patients, EGFR TKI therapy leads to an accumulation of immunosuppressive macrophages, which is strictly treatment-dependent and fully reversible upon treatment cessation or progressive disease, respectively. Quiescent DTP cells directly drive the recruitment and immunosuppressive reprogramming of monocytes and macrophages through a YAP-driven secretome, and the DTP-reprogrammed monocytes suppress T cell proliferation and effector functions in vitro. Co-targeting YAP with a TEAD inhibitor ORM-47286 rewires the DTP secretome and inhibits macrophage reprogramming in vitro, and prevents immunosuppressive macrophage accumulation and improves the efficacy of EGFR TKI therapy in immunocompetent mouse models. Our findings highlight the previously unappreciated role of DTP cells in modulating the tumor microenvironment in on-treatment tumors, and position the treatment-induced YAP/TEAD activity in DTP cells as an important driver of adaptive immunosuppression during EGFR-targeted therapy.

cancer biology↗

bioRxiv2023

The histone modifier KAT2A presents a selective target in a subset of well-differentiated microsatellite-stable colorectal cancers

BackgroundLysine acetyltransferase 2A (KAT2A) plays a pivotal role in epigenetic gene regulation across various types of cancer. In colorectal cancer (CRC), upregulation of KAT2A is associated with a more aggressive phenotype. Our study aims to elucidate the molecular underpinnings of KAT2A dependency in CRC and assess the consequences of KAT2A depletion. MethodsWe conducted a comprehensive analysis by integrating CRISPR-Cas9 screening data with genomics, transcriptomics, and global acetylation patterns in CRC cell lines to pinpoint molecular markers indicative of KAT2A dependency. Additionally, we characterized the phenotypic effect of a CRISPR-Cas9-mediated KAT2A knockout and chemical inhibition of KAT2A in CRC cell lines and patient- derived 3D spheroid cultures. ResultsOur findings reveal that KAT2A dependency is closely associated with a lower mutational burden and increased differentiation grade in CRC cell lines, independent of the KAT2A expression levels. KAT2A dependent CRC cell lines display enriched H3K27ac marks at gene loci linked to enterocytic differentiation. Loss of KAT2A leads to decreased cell growth and viability, downregulation of proliferation- and stem cell-associated genes, and induction of differentiation markers. ConclusionA specific subset of CRCs with a more differentiated phenotype relies on KAT2A. For these CRC cases, KAT2A might represent a promising novel therapeutic target.

cancer biology↗