2. Academic Validation
  3. Drug screening in 3D microtumors reveals DDR1/2-MAPK12-GLI1 as a vulnerability in cancer-associated fibroblasts

Drug screening in 3D microtumors reveals DDR1/2-MAPK12-GLI1 as a vulnerability in cancer-associated fibroblasts

  • Cell Rep Med. 2025 Sep 19:102357. doi: 10.1016/j.xcrm.2025.102357.
Nao Nishida-Aoki 1,  Songli Zhu 1,  Marina Chan 1,  Yuqi Kang 1,  Maihi Fujita 2,  Xiuyun Jiang 3,  Maxwell McCabe 4,  Joel M Vaz 1,  Nancy E Davidson 5,  Cyrus M Ghajar 6,  Kirk Hansen 4,  Alana L Welm 2,  Venu G Pillarisetty 3,  Taranjit S Gujral 7
Affiliations

Affiliations

  • 1 Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • 2 Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
  • 3 Department of Surgery, University of Washington, Seattle, WA, USA.
  • 4 Department of Biochemistry and Molecular Genetics, University of Colorado, Denver, CO, USA.
  • 5 Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • 6 Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • 7 Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. Electronic address: tgujral@fredhutch.org.
PMID: 40975064 DOI: 10.1016/j.xcrm.2025.102357
Abstract

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 confirm the effectiveness of doramapimod, a compound that reduces microtumor viability and suppresses tumor growth in mouse models but 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.

Keywords

CAF; functional screening; hedgehog pathway; kinase signaling; microtumor; precision oncology; tumor microenvironment.

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