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

Area of Science:

• Oncology
• Cancer Biology
• Drug Discovery

Background:

• Tumor microenvironment interactions are crucial for cancer progression and treatment outcomes.
• Conventional 2D cell culture models may not accurately reflect in vivo tumor complexity.

Purpose of the Study:

• To compare drug efficacy between 2D cancer cell lines and 3D tumor tissues.
• To identify novel therapeutic targets within the tumor microenvironment.

Main Methods:

• Comparative drug screening using 2D cell lines and 3D microtumors.
• In vivo efficacy studies of doramapimod in mouse models.
• Mechanistic studies involving kinase inhibition (DDR1/2, MAPK12) and extracellular matrix (ECM) production in cancer-associated fibroblasts (CAFs).

Main Results:

• On average, three times more drugs were effective in 3D microtumors compared to 2D cultures.
• Doramapimod reduced microtumor viability and suppressed tumor growth in mice, but not in 2D cell cultures.
• Doramapimod targets DDR1/2 and MAPK12 kinases in CAFs, decreasing ECM production and enhancing interferon signaling.
• The DDR1/2-MAPK12-GLI axis in CAFs regulates ECM independently of canonical hedgehog signaling.
• Inhibition of this axis enhanced chemotherapy and immunotherapy in patient tumor slices and preclinical models.

Conclusions:

• 3D tumor models are superior to 2D models for identifying effective cancer drugs.
• The DDR1/2-MAPK12-GLI axis in CAFs is a critical regulator of the tumor microenvironment.
• Targeting this axis represents a promising strategy to improve cancer treatment efficacy, including chemotherapy and immunotherapy.