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Divergently evolved FOXA1 mutations drive prostate tumorigenesis or therapy-resistant intra-luminal plasticity [Single-cell Multiome]

GSE280876 Mus musculus (mouse) Single-cell RNA-seq 54 samples Submitted 2025/07/02 Platform GPL24247
At a glance

Single-cell RNA-seq · mouse · 54 samples

What it is
Single-cell RNA-seqGene activity measured in thousands of individual cells, so cell types can be told apart.
Organism
Mus musculus (mouse)
Samples
54 samples: 46 distinct titles, 4 of them repeatedGroups are read from the sample names, not from the paper. Check the list below.
Data you can get
A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Paper
Divergent FOXA1 mutations drive prostate tumorigenesis and therapy-resistant cellular plasticityScience (New York, N.Y.) · 2025
Summary (written by the submitters)
FOXA1 is recurrently altered in hormone-driven malignancies, with activating hotspot mutations detected in 10-40% of primary prostate cancers based on ethnicity. Yet, the tumorigenic potential and pathobiology of FOXA1 remain unexplored in vivo. Here, we generated and characterized knock-in mouse models harboring FOXA1 mutant transgenes that represent distinct classes of activating mutations.
Read the full summary ↓
Our findings reveal that FOXA1 class 1 mutations (i.e., wing 2 alterations) in a Trp53-null background, drive high-grade, invasive luminal adenocarcinoma with full penetrance by 40 weeks of age. These hyperproliferative lesions retain luminal characteristics, gain expression of NSD2, and regress upon androgen withdrawal—mirroring features of primary human prostate adenocarcinomas. Mechanistically, class 1 mutants aberrantly activate mTORC1/2 signaling and reprogram androgen receptor (AR) activity by expanding the enhancer landscape at non-canonical chimeric AR-half elements enriched in patient tumors. In contrast, FOXA1 class 2 mutations (i.e., C-terminal truncations) do not drive transformation but induce intra-luminal plasticity in androgen-intact normal tissues, which is otherwise triggered in response to castration. Class 2 mutants lead to a 10- to 20-fold expansion of Ar+/Ck8+ luminal epithelia expressing stem/progenitor markers such as Trop2, Ck4, and Psca. Mechanistically, class 2 mutants maintain AR activity while de-compacting over 40,000 new cis-regulatory elements bound by Klf5 and AP-1 transcription factors to activate stemness and WNT gene programs. Class 2-mutant-expressing prostate epithelial cells resist castration-induced atrophy, remain proliferative in androgen-deprived conditions, and form organoids and allografts at higher frequencies. Additionally, metastatic prostate tumors from patients harboring class 2 mutations show elevated KLF5 expression and stemness signatures. Collectively, our data establish FOXA1 as a critical oncogene in both primary and advanced AR-dependent prostate cancers, revealing its functional versatility in driving either tumor initiation or therapy resistance depending on the mutation class.
Published in
Divergent FOXA1 mutations drive prostate tumorigenesis and therapy-resistant cellular plasticity
Eyunni S, Mannan R, Zhang Y et al. · Science (New York, N.Y.) 2025 · PMID 40570057 · doi:10.1126/science.adv2367
This dataset
Open GSE280876 in finder → Find more mouse RNA-seq datasets →
Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓
2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE280876_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓
3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: Single-cell studies usually ship their counts as 10x files (matrix.mtx, barcodes.tsv, features.tsv), an .h5 file, or an .rds / .h5ad object that Seurat or Scanpy can open. Look for those among the supplementary files.

Also filed as BioProject PRJNA1180958 and SRA study SRP542641. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 40570057) ↗
Study design
46 distinct titles, 4 of them repeated
FOXA1 R265-71del+/+,TP53+/+,Pb-Cre ×4 FOXA1 R265-71del+/+,TP53+/+,Pb-Cre+ ×4 P358fs-/-Cre-(ctrl) ×2 P358fs+/-Cre+(case) ×2

How we read this: Read from 54 sample titles: 46 distinct titles with little repetition. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study

+ 14 more — browse all 54 samples with per-sample file links →

Datasets on a similar topic

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