GEO series

Molecular dynamics driving phenotypic divergence among KRAS mutants in pancreatic tumorigenesis [ATAC-Seq]

GSE279088 Mus musculus Genome binding/occupancy profiling by high throughput sequencing 74 samples Submitted 2026/04/01 Platform GPL21103Platform GPL30172Platform GPL17021

Summary

Inflammation in the context of pancreatic injury drives acinar-to-ductal metaplasia (ADM), a cell state that can be hijacked by mutant Kras to drive the formation of pancreatic cancer. ADM has been described alternatively to bear progenitor features, but the extent to which lineage reversion is a broad feature of the response to injury and early tumorigenesis – particularlyacross the different mutant Kras alleles – remains poorly understood. Herein we implement novel Ptf1a-tdTomato mice to characterize early and late pancreatic progenitors to serve as benchmarks that define cell fate decisions in the context of inflammatory injury and initiation. In so doing, we define ADM as a mixed-lineage transcriptomic and epigenetic state, harboring ductal features but also featuring a lineage reversion to a late progenitor program. By contrast, while inducible mutant Kras alone is able to induce oncogenic gene expression, it does little to alter chromatin in the absence of injury. The most frequent Kras mutant alleles – G12D, G12V, and G12R – display differential cooptation of the injury-induced mixed-lineage state, with mutant KrasG12D able to form ADM and PanIN more robustly than either KrasG12V or KrasG12R. In particular, KrasG12R fails to promote phenotypic transformation on its own or even in concert with inflammatory injury. Whereas KrasG12Dand injury induce enhancer reprogramming at AP-1 chromatin and a lineage reversion to resemble early progenitors, KrasG12Rcan initiate but not sustain the key cell-intrinsic transcriptional and epigenetic programs characteristic of neoplasia. In KrasG12R we identify a decrease in Rac1 signaling, not AKT activation, as the key molecular defect. Together, these data demonstrate that the PDAC-associated Kras variants are not functionally equivalent and distinctly drive lineage reversion and epigenetic reprogramming, such that allele-specific approaches will be essential to therapeutic targeting in pancreatic cancer.

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Direct links to NCBI, no account and no request form: the whole study as GSE279088_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 74 samples. Raw sequencing reads are also available from ENA.

Whole study · RAW.tar ↓ Series matrix ↓ All supplementary files ↗ Raw reads on ENA ↗

Also filed as BioProject PRJNA1170339 and SRA study SRP537210. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗

Study design

11 conditions, mostly with about 4 replicates each

wk3_KrasG12D_Caerulein_B ×6 d2_KrasG12D_Caerulein_B ×4 d2_KrasG12R_Caerulein_B ×4 d2_KrasG12Vgeo_Caerulein_B ×4 d2_KrasWT_Caerulein_B ×4 ductal ×4 earlyProgenitor_PT42A_2 ×2 earlyProgenitor_PT43A_1 ×2 +7 more

Supports a between-group comparison across 36 samples.

11 replicated groups read from the first 40 of 74 sample titles; they account for 36 of them. Check it against the sample list below before relying on it.

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