GEO series
Drug Screening in 3D Microtumors Reveals DDR1/2-MAPK12-GLI1 as a Vulnerability in Cancer-Associated Fibroblasts
GSE304108
Mus musculus; Homo sapiens
Expression profiling by high throughput sequencing
29 samples
Submitted 2025/08/04
Platform GPL16791Platform GPL17021
Summary
Interactions between cancer cells and surrounding stromal cells are critical for tumor biology and treatment response. We compare drug screening results from conventional 2D cancer cell lines with 3D tumor tissues and find that, on average, three times more drugs are effective in 3D microtumors. We confirmed the effectiveness of doramapimod, a compound that reduces 3D microtumor viability and suppresses tumor growth in mouse models, has no effect on cancer cell growth in monolayers. Mechanistically, doramapimod targets DDR1/2 and MAPK12 kinases in cancer-associated fibroblasts (CAFs), decreasing extracellular matrix (ECM) production and enhancing interferon signaling. These kinases regulate ECM through GLI1 activity in CAFs, independently of canonical hedgehog signaling. Inhibiting the DDR1/2-MAPK12-GLI axis enhances the effectiveness of chemotherapy and immunotherapy in patient tumor slices and preclinical models. These findings highlight the importance of DDR1/2-MAPK12-GLI axis in CAF function and demonstrate the utility of 3D tissue models in identifying microenvironment-specific therapeutic targets.
Published in
Nishida-Aoki N, Zhu S, Chan M et al.
· Cell reports. Medicine 2025
· PMID 40975064
· doi:10.1016/j.xcrm.2025.102357
This dataset
Download
Direct links to NCBI, no account and no request form: the whole study as GSE304108_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 29 samples. Raw sequencing reads are also available from ENA.
Also filed as BioProject PRJNA1298926 and SRA study SRP604732. Searching any of these in the dataset finder brings you back here.
Study design
14 conditions, mostly in duplicate
E0771 Doramapimod Treated RNA ×3
KPC1 Vehicle Control RNA ×2
KPC1 Doramapimod Treated RNA ×2
E0771 Vehicle Control RNA ×2
Breast CAFs DMSO RNA ×2
Breast CAFs Doramapimod High RNA ×2
Breast CAFs DDR1/2, MAPK12 Non-targeting Cont… ×2
Breast CAFs DDR1 Knockdown RNA ×2
+6 more
Supports a case/control comparison: 15 samples read as cases, 12 as controls.
14 replicated groups read from 29 sample titles; they account for 29 of them. Check it against the sample list below before relying on it.
Samples in this study
0 selected
- GSM9143690 KPC1 Vehicle Control RNA Replicate 1
- GSM9143691 KPC1 Vehicle Control RNA Replicate 2
- GSM9143692 KPC1 Doramapimod Treated RNA Replicate 1
- GSM9143693 KPC1 Doramapimod Treated RNA Replicate 2
- GSM9143694 E0771 Vehicle Control RNA Replicate 1
- GSM9143695 E0771 Vehicle Control RNA Replicate 2
- GSM9143696 E0771 Doramapimod Treated RNA Replicate 1
- GSM9143697 E0771 Doramapimod Treated RNA Replicate 2
- GSM9143698 E0771 Doramapimod Treated RNA Replicate 3
- GSM9143699 Breast CAFs DMSO RNA Replicate 1
- GSM9143700 Breast CAFs DMSO RNA Replicate 2
- GSM9143701 Breast CAFs Doramapimod High RNA Replicate 1
- GSM9143702 Breast CAFs Doramapimod High RNA Replicate 2
- GSM9143703 Breast CAFs DDR1/2, MAPK12 Non-targeting Control RNA Replicate 1
- GSM9143704 Breast CAFs DDR1/2, MAPK12 Non-targeting Control RNA Replicate 2
- GSM9143705 Breast CAFs DDR1 Knockdown RNA Replicate 1
- GSM9143706 Breast CAFs DDR1 Knockdown RNA Replicate 2
- GSM9143707 Breast CAFs DDR2 Knockdown RNA Replicate 1
- GSM9143708 Breast CAFs DDR2 Knockdown RNA Replicate 2
- GSM9143709 Breast CAFs MAPK12 Knockdown RNA Replicate 1
- GSM9143710 Breast CAFs MAPK12 Knockdown RNA Replicate 2
- GSM9143711 Breast CAFs DMSO Replicate 1
- GSM9143712 Breast CAFs DMSO Replicate 2
- GSM9143713 Breast CAFs Gant61 Treated RNA Replicate 1
- GSM9143714 Breast CAFs Gant61 Treated RNA Replicate 2
- GSM9143715 Pancreas CAFs DMSO Replicate 1
- GSM9143716 Pancreas CAFs DMSO Replicate 2
- GSM9143717 Pancreas CAFs Gant61 Treated RNA Replicate 1
- GSM9143718 Pancreas CAFs Gant61 Treated RNA Replicate 2
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