GEO series
Opposing lineage specifiers induce a pro-tumor hybrid-identity state in lung adenocarcinoma [ChIP-seq]
GSE281961
Homo sapiens; Mus musculus
Genome binding/occupancy profiling by high throughput sequencing
60 samples
Submitted 2025/06/13
Platform GPL24247Platform GPL24676
Summary
Lineage plasticity is critical for tumor progression and therapy resistance, but the molecular mechanisms underlying cell identity shifts in cancer remain poorly understood. In lung adenocarcinoma (LUAD), the loss of pulmonary lineage fidelity and acquisition of alternate identity programs converge on hybrid-identity (hybrid-ID) states which are postulated to be key intermediates in LUAD evolution and are characterized by the co-activation of developmentally incompatible identity programs within individual cells. Here, we uncover a previously unrecognized role for the gastrointestinal transcriptional regulator HNF4α in driving tumor growth and hybrid-ID states in LUAD. In LUAD cells expressing the lung lineage specifier NKX2-1, HNF4α induces a GI/liver-like state by directly binding and activating its canonical targets. HNF4α also disrupts NKX2-1 genomic localization and dampens pulmonary identity within hybrid-ID LUAD. We show that this hybrid-ID state is maintained by sustained by RAS/MEK signaling. Inhibition of the RAS/MEK signaling cascade augments NKX2-1 chromatin binding at pulmonary-specific genes and induces drug resistance-associated pulmonary signatures. Finally, we demonstrate that HNF4α depletion sensitizes LUAD cells to KRASG12D inhibition. Collectively, our data show that co-expression of opposing lineage specifiers is a novel mechanism of identity dysregulation in LUAD that influences both tumor progression and response to targeted therapy.
Published in
Fort G, Arnold H, Camolotto SA et al.
· Genes & development 2025
· PMID 40506247
· doi:10.1101/gad.352742.125
This dataset
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Direct links to NCBI, no account and no request form: the whole study as GSE281961_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 60 samples. Raw sequencing reads are also available from ENA.
Also filed as BioProject PRJNA1186328 and SRA study SRP545352. Searching any of these in the dataset finder brings you back here.
Study design
20 conditions, mostly in duplicate
3154_EtOH_Input ×2
3154_EtOH_HNF4a ×2
3154_EtOH_NKX2-1 ×2
3154_EtOH_FoxA1 ×2
3154_EtOH_FoxA2 ×2
3154_4OHT_Input ×2
3154_4OHT_NKX2-1 ×2
3154_4OHT_FoxA1 ×2
+12 more
Supports a between-group comparison across 40 samples.
20 replicated groups read from the first 40 of 60 sample titles; they account for 40 of them. Check it against the sample list below before relying on it.
Samples in this study
0 selected
- GSM8633583 3154_EtOH_Input_Replicate1
- GSM8633584 3154_EtOH_Input_Replicate2
- GSM8633585 3154_EtOH_HNF4a_Replicate1
- GSM8633586 3154_EtOH_HNF4a_Replicate2
- GSM8633587 3154_EtOH_NKX2-1_Replicate1
- GSM8633588 3154_EtOH_NKX2-1_Replicate2
- GSM8633589 3154_EtOH_FoxA1_Replicate1
- GSM8633590 3154_EtOH_FoxA1_Replicate2
- GSM8633591 3154_EtOH_FoxA2_Replicate1
- GSM8633592 3154_EtOH_FoxA2_Replicate2
- GSM8633593 3154_4OHT_Input_Replicate1
- GSM8633594 3154_4OHT_Input_Replicate2
- GSM8633595 3154_4OHT_NKX2-1_Replicate1
- GSM8633596 3154_4OHT_NKX2-1_Replicate2
- GSM8633597 3154_4OHT_FoxA1_Replicate1
- GSM8633598 3154_4OHT_FoxA1_Replicate2
- GSM8633599 3154_4OHT_FoxA2_Replicate1
- GSM8633600 3154_4OHT_FoxA2_Replicate2
- GSM8633601 H1651_Input_Replicate1
- GSM8633602 H1651_Input_Replicate2
- GSM8633603 H1651_HNF4a_Replicate1
- GSM8633604 H1651_HNF4a_Replicate2
- GSM8633605 H1651_NKX2-1_Replicate1
- GSM8633606 H1651_NKX2-1_Replicate2
- GSM8633607 H1651_FoxA1_Replicate1
- GSM8633608 H1651_FoxA1_Replicate2
- GSM8633609 3311_Control_Input_Replicate1
- GSM8633610 3311_Control_Input_Replicate2
- GSM8633611 3311_Control_NKX2-1_Replicate1
- GSM8633612 3311_Control_NKX2-1_Replicate2
- GSM8633613 3311_Control_HNF4a_Replicate1
- GSM8633614 3311_Control_HNF4a_Replicate2
- GSM8633615 3311_Control_FoxA1_Replicate1
- GSM8633616 3311_Control_FoxA1_Replicate2
- GSM8633617 3311_MEKi_Input_Replicate1
- GSM8633618 3311_MEKi_Input_Replicate2
- GSM8633619 3311_MEKi_NKX2-1_Replicate1
- GSM8633620 3311_MEKi_NKX2-1_Replicate2
- GSM8633627 1027B_Control_Input_Replicate1
- GSM8633628 1027B_Control_Input_Replicate2
+ 20 more — browse all 60 samples with per-sample file links →
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