Omics · study · 2026
HNF4a controls growth, identity and response to KRAS inhibition in IMA [scRNA-seq]
Listed in NCBI GEO
Cellular plasticity is a key feature of cancer that enables tumor cells to switch lineage identities, driving disease progression and resistance to therapy.
Description
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.
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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.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE294nnn/GSE294571 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE294571 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1250516 ncbi.nlm.nih.gov/bioproject/PRJNA1250516 ↗
project · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Mus musculus
- From keywords
- Life Sciences
- Inferred from text
- Cancer 75% · Disease 75% · Single-cell RNA sequencing 65%
Provenance · 1 source records, 10 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE294571 | 13 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:cancer | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[disease].local:disease:disease | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[modality].local:modality:single-cell-rna-seq | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (65%) |
| concepts[organism].NCBITaxon:10090 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |