PXD066684-1

PXD066684 is an original dataset announced via ProteomeXchange.

Title	Drug Screening in 3D Microtumors Reveals DDR1/2-MAPK12-GLI1 as a Vulnerability in Cancer-Associated Fibroblasts
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-08-15
AnnouncementXML	Submission_2025-08-15_05:44:52.308.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD066684
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Kirk Hansen
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	2-pyrrolidone-5-carboxylic acid (Gln); acetylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-28 13:58:53	ID requested
⏵ 1	2025-08-15 05:44:52	announced

10.6019/PXD066684;

submitter keyword: drug screening,cancer, fibroblasts, doramapimod, extracellular matrix

Taranjit S Gujral
contact affiliation	Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Pharmacology, University of Washington, Seattle, WA, USA
contact email	tgujral@fredhutch.org
lab head
Kirk Hansen
contact affiliation	Univeristy of Colorado
contact email	kirk.hansen@cuanschutz.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD066684
     1. Label: PRIDE project
     2. Name: Drug Screening in 3D Microtumors Reveals DDR1/2-MAPK12-GLI1 as a Vulnerability in Cancer-Associated Fibroblasts