GEO series

Divergently evolved FOXA1 mutations drive prostate tumorigenesis or therapy-resistant intra-luminal plasticity [ChIP-seq]

GSE280834 Mus musculus (mouse) ChIP-seq / ATAC-seq (genome binding and open chromatin) 17 samples Submitted 2025/07/02 Platform GPL17021

At a glance

ChIP-seq / ATAC-seq (genome binding and open chromatin) · mouse · 17 samples

What it is: ChIP-seq / ATAC-seq (genome binding and open chromatin)Where proteins bind the genome, or which regions are open and active.
Organism: Mus musculus (mouse)
Samples: 17 samples: 17 samples, each with a distinct title — no replicated groupsGroups 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 GSE280834 in finder → Find more mouse ChIP / ATAC / CUT&Tag 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 GSE280834_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: Look for peak files (.bed, .narrowPeak) and signal tracks (.bigWig) among the supplementary files; the raw reads are on ENA.

Also filed as BioProject PRJNA1180882 and SRA study SRP542558. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗ Paper (PMID 40570057) ↗

Study design

17 samples, each with a distinct title — no replicated groups

Any grouping that defines a comparison lives in the sample characteristics, which GEO records separately from the titles.

How we read this: Read from 17 sample titles: 17 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

GSM8606350 Ms1706_Control_AR
GSM8606351 Ms1706_CRE_AR
GSM8606352 Ms2114_Control_KLF5
GSM8606353 Ms2114_Control_TSF
GSM8606354 Ms2114_CRE_CST
GSM8606355 Ms2114_CRE_KLF5
GSM8606356 Ms1947_Control_TFS
GSM8606357 Ms1947_CRE_CST
GSM9035766 Ms_3888_sgNC_5_H3K36me2_CST
GSM9035767 Ms_3888_sgNsd2_10_H3K36me2_CST
GSM9035768 Ms_1947_CRE_TFS
GSM9035769 Ms_1706_control_TFS
GSM9035770 Ms_1706_CRE_CST
GSM9035771 Ms_3888_sgNC_5_Ar
GSM9035772 Ms_3888_sgNsd2_10_Ar
GSM9035773 Ms_1947_control_Ar
GSM9035774 Ms_1947_CRE_Ar

Datasets on a similar topic

GSE282406 Divergently evolved FOXA1 mutations drive prostate tumorigenesis or therapy-resistant intra-luminal plasticity 113 samples shares foxa1, therapy-resistant, tumorigenesis, intra-luminal, divergently, plasticity, mutations, prostate
GSE280876 Divergently evolved FOXA1 mutations drive prostate tumorigenesis or therapy-resistant intra-luminal plasticity [Single-cell Multiome] 54 samples shares foxa1, therapy-resistant, tumorigenesis, intra-luminal, divergently, plasticity, mutations, prostate
GSE280835 Divergent FOXA1 mutations drive prostate tumorigenesis or therapy-resistant intra-luminal plasticity [RNA-Seq] 38 samples shares foxa1, therapy-resistant, tumorigenesis, intra-luminal, plasticity, mutations, prostate
GSE285574 Foxa1 mutations co-opt nascent transcription factor networks in partnership with androgen receptor to enhance prostate tumorigenicity 38 samples shares foxa1, mutations, prostate
GSE313915 FOXA1 loss drives basal/squamous de-differentiation of prostate cancer and induces an immunosuppressive tumor microenvironment 12 samples shares foxa1, prostate
GSE224825 Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis [Prox1 OE MEF/4in1 ATAC-seq] 12 samples shares tumorigenesis, plasticity
GSE300614 Cooperativity between Ras pathway mutations in colonic tumorigenesis 27 samples shares tumorigenesis, mutations
GSE224831 Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis [Prox1 OE iHep Timecourse RNA-seq] 16 samples shares tumorigenesis, plasticity

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