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Targeting ROCK2 improves macromolecular permeability in a 3D fibrotic pancreatic cancer microenvironment model
Hiroyoshi Y Tanaka1, Takuya Nakazawa2, Takuya Miyazaki3
1Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama-shi, Okayama 700-8530, Japan.
Summary
Targeting the TGFβ/ROCK2/YAP pathway in pancreatic stellate cells normalizes the tumor stroma. This improves nanomedicine penetration and efficacy in pancreatic cancer treatment.
Area of Science:
- Oncology
- Cancer Biology
- Biomedical Engineering
Background:
- Pancreatic cancer features a dense fibrotic stroma that impedes nanomedicine delivery and reduces treatment effectiveness.
- Fibrosis involves abnormal extracellular matrix (ECM) organization, driven by pancreatic stellate cells (PSCs).
Purpose of the Study:
- To investigate if targeting ECM-organization signaling pathways in PSCs can enhance nanomedicine penetration into pancreatic tumors.
Main Methods:
- Utilized a 3D cell culture model of the pancreatic cancer microenvironment.
- Investigated the effects of TGFβ and ROCK1/2 inhibition on ECM organization and macromolecular permeability.
- Employed isoform-specific inhibitors and siRNAs to target ROCK1/2 and YAP.
- Assessed YAP nuclear localization in fibroblasts co-cultured with pancreatic cancer cells.
Main Results:
- Inhibition of TGFβ or ROCK1/2 normalized ECM organization and improved macromolecular permeability.
- Targeting ROCK2, but not ROCK1, was sufficient for normalizing ECM and enhancing permeability.
- ROCK2 inhibition reduced YAP nuclear localization.
- Inhibition or knockdown of YAP also normalized ECM organization and improved permeability.
Conclusions:
- The TGFβ/ROCK2/YAP signaling axis is a potential therapeutic target in pancreatic cancer.
- Normalizing ECM organization via this axis can improve macromolecular permeability.
- This approach may enhance the efficacy of nanomedicines in pancreatic cancer therapy.
