GEO series
ZEB2 is a Master Switch Controlling the Tumor-Associated Macrophage Program [in vitro]
GSE269187
Mus musculus
Expression profiling by high throughput sequencing
17 samples
Submitted 2025/03/10
Platform GPL24247
Summary
Tumor-associated macrophages (TAMs) are major players in regulating the immunosuppressive tumor environment, and their abundance is highly correlated with poor clinical outcomes. Here, we constructed a TAM regulatory network by integrating scRNA-seq data across human solid tumors with a dedicated CRISPR knockout screen. Using a deep generative model capable of learning a local representation for each candidate regulator, we constructed a gene perturbation network that linked individual target genes with prototypical functional modules in TAMs. We identified non-redundant pathways regulating distinct TAM functions, showing modular circuitry. For instance, the complement module is repressed by Stat6, Zeb2, Gpnmb, and Spp1, while the Tgfbr1-Smad2/4 pathway induces this program in TAMs. Importantly, we identified Zeb2 as the master regulator of pro-tumor functions in TAMs, orchestrating the suppression of type I interferon response and antigen presentation alongside the activation of immune suppression programs. Genetic ablation of Zeb2 reprogrammed TAMs identity on chromatin, RNA, and protein levels. In human tumors with high macrophage content, ZEB2 expression was associated with poor prognosis in solid cancers, including lung and bladder. Functional macrophage coculturing assays defined Zeb2 as a critical regulator of TAM immunosuppression activity by inhibiting T cell proliferation and activation. Selective in vivo targeting of Zeb2 in macrophages using a CpGsiRNAZeb2 DNA hybrid reprogrammed TAMs and mobilized systematic anti-tumoral T cell responses, achieving complete tumor clearance as a monotherapy. Overall, our study generated a detailed genetic roadmap of TAM gene circuits and identified ZEB2 as a master switch of TAMs with potential therapeutic implications for macrophage-based immunotherapies.
Published in
Sheban F, Phan TS, Xie K et al.
· Cancer cell 2025
· PMID 40215981
· doi:10.1016/j.ccell.2025.03.021
This dataset
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Direct links to NCBI, no account and no request form: the whole study as GSE269187_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 17 samples. Raw sequencing reads are also available from ENA.
Also filed as BioProject PRJNA1120478 and SRA study SRP512056. Searching any of these in the dataset finder brings you back here.
Study design
17 × BMDMs, AB
Supports a between-group comparison across 17 samples.
1 replicated groups read from 17 sample titles; they account for 17 of them. Check it against the sample list below before relying on it.
Samples in this study
0 selected
- GSM8307779 BMDMs, AB12212
- GSM8307780 BMDMs, AB12213
- GSM8307781 BMDMs, AB12214
- GSM8307782 BMDMs, AB12215
- GSM8307783 BMDMs, AB12216
- GSM8307784 BMDMs, AB12217
- GSM8307785 BMDMs, AB12219
- GSM8307786 BMDMs, AB12220
- GSM8307787 BMDMs, AB12221
- GSM8307788 BMDMs, AB12222
- GSM8307789 BMDMs, AB12223
- GSM8307790 BMDMs, AB12224
- GSM8307791 BMDMs, AB12225
- GSM8307792 BMDMs, AB12226
- GSM8307793 BMDMs, AB12233
- GSM8307794 BMDMs, AB12234
- GSM8307795 BMDMs, AB12235
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