GEO series
HNF4a controls growth, identity and response to KRAS inhibition in IMA [ChIP- seq]
GSE294572
Homo sapiens; Mus musculus
Genome binding/occupancy profiling by high throughput sequencing
38 samples
Submitted 2026/04/23
Platform GPL24247Platform GPL24676
Summary
Cellular plasticity is a key feature of cancer that enables tumor cells to switch lineage identities, driving disease progression and resistance to therapy. In invasive mucinous adenocarcinoma (IMA), a pronounced pulmonary-to-gastric lineage switch occurs as NKX2.1 is lost and HNF4α, a master regulator of gastric differentiation, is upregulated. Although absent in normal alveolar type 2 cells, HNF4α is aberrantly expressed in most IMA tumors. In this study, we investigate the role of HNF4α within established IMAs and find that it directly activates a gastric differentiation program, particularly in pit cells. Loss of HNF4α disrupts this program and permits FOXA1 and FOXA2 to bind new regulatory sites, leading to the upregulation of neuronal and liver-like gene modules. In light of the poor response of mucinous tumors to KRAS inhibitors, we investigated whether HNF4α modulates sensitivity to KRASG12D targeted therapy. Treatment with MRTX1133 revealed that loss of HNF4α significantly increases IMA sensitivity by reducing the IC50 in vitro and enhancing tumor regression in vivo. Mechanistically, HNF4α deletion impairs cell-cycle progression in drug-tolerant persister cells, while tumors retaining HNF4α maintain these cell-cycle regulators despite KRAS inhibition, promoting persister cell survival. Our findings establish HNF4α as a critical driver of IMA biology governing both gastric differentiation and resistance to KRAS inhibitors and support the development of combination strategies to overcome therapeutic resistance in IMA.
This dataset
Download
Direct links to NCBI, no account and no request form: the whole study as GSE294572_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 38 samples. Raw sequencing reads are also available from ENA.
Also filed as BioProject PRJNA1250515 and SRA study SRP578440. Searching any of these in the dataset finder brings you back here.
Study design
38 conditions, each sampled once — no replicated groups
Read from 38 sample titles: 38 distinct titles with little repetition. Check it against the sample list below before relying on it.
Samples in this study
0 selected
- GSM8911548 20899X1_1311G#5_KN_input_rep1
- GSM8911549 20899X2_1311G#5_KNH_input_rep1
- GSM8911550 20899X3_1311G#5_KN_FOXA1_rep1
- GSM8911551 20899X4_1311G#5_KNH_FOXA1_rep1
- GSM8911552 21021X1_1311G#5_KN_FOXA1_rep2
- GSM8911553 21021X2_1311G#5_KNH_FOXA1_rep2
- GSM8911554 21021X3_1311g#5_KN_input_rep2
- GSM8911555 21021X4_1311G#5_KNH_input_rep2
- GSM8911556 23754X1_1311g#5_KN Hnf4a_rep1
- GSM8911557 23754X2_1311g#5_KN_Input_rep1
- GSM8911558 23754X3_1311g#5_KN_Hnf4a_rep2
- GSM8911559 23754X4_1311g#5_KN_input_rep2
- GSM8911560 24131X1_429A_KN_input_rep1
- GSM8911561 24131X2_429A_KN_Hnf4a_rep1
- GSM8911562 24131X3_429A_KN_input_rep2
- GSM8911563 24131X4_429A_KN_Hnf4a_rep2
- GSM8911564 24137X1_GEMM_KN_HED798_FOXA1_rep1
- GSM8911565 24137X2_GEMM_KN_HED798_Hnf4a_rep1
- GSM8911566 24137X3_GEMM_KN_HED798_input_rep1
- GSM8911567 24515X1_GEMM_KN_HED934_input
- GSM8911568 24515X2_GEMM_KN_HED934_FOXA1_rep2
- GSM8911569 24515X3_GEMM_KN_HED934_FOXA2_rep1
- GSM8911570 24515X4_GEMM_KN_HED934_Hnf4a_rep2
- GSM8911571 24515X5_GEMM_KNH_HED968_input
- GSM8911572 24515X6_GEMM_KNH_HED968_FOXA1_rep2
- GSM8911573 24515X7_GEMM_KN_HED814_input
- GSM8911574 24515X8_GEMM_KN_HED814_FOXA2_rep2
- GSM8911575 24289X1_GEMM_KNH_HED931_FOXA1_rep1
- GSM8911576 24289X2_GEMM_KNH_HED931_FOXA2_rep1
- GSM8911577 24289X3_GEMM_KNH_HED931_input
- GSM8911578 24289X4_GEMM_KNH_HED897_input
- GSM8911579 24289X6_GEMM_KNH_HED897_FOXA2_rep2
- GSM9689277 25736X1_HCI_IMA03_KN_input_rep1
- GSM9689278 25736X2_HCI_IMA03_KN_Hnf4a_rep1
- GSM9689279 25736X3_HCI_IMA03_KN_FOXA1_rep2
- GSM9689280 25736X4_HCI_IMA03_KN_Hnf4a_rep2
- GSM9689281 25798X1_HCI_IMA03_KN_input_rep2
- GSM9689282 25798X2_HCI_IMA03_KN_FOXA1_rep1
Similar datasets
- GSE287736 Sex-specific KDM6A-HNF4A-CREBH network controls lipoprotein cholesterol metabolism and atherosclerosis via epigenetic reprograming of hepatocytes 138 samples
- GSE229439 Tracing functional (epi)genomic imprints and their evolutionary origins in human defense antiviral cellular response (ChIP-Seq) 85 samples
- GSE292300 A core transcriptional regulatory circuitry controls super-enhancer-driven activation of LGR5 in colorectal cancer: ChIP-seq 76 samples
- GSE281961 Opposing lineage specifiers induce a pro-tumor hybrid-identity state in lung adenocarcinoma [ChIP-seq] 60 samples
- GSE288595 Tracing functional (epi)genomic imprints and their evolutionary origins in human defense antiviral cellular response (ChIP-seq III) 14 samples
- GSE320163 Minimizing far-extending chromatin perturbation in genome editing preserves stem cell identity [ATAC-Seq] 377 samples
- GSE245731 HNF4G and FOXA1 are context-specific drivers of pancreatic cancer progression [ChIP-seq] 172 samples
- GSE260742 DOT1L provides transcriptional memory through PRC1.1 antagonism [ChIP-Seq] 158 samples
Share this dataset
Metadata from NCBI GEO, cached and refreshed periodically — the NCBI page above is authoritative. Downloads link straight to NCBI/ENA; nothing is proxied through BioTransfer.