| Budget Amount *help |
¥42,640,000 (Direct Cost: ¥32,800,000、Indirect Cost: ¥9,840,000)
Fiscal Year 2019: ¥12,220,000 (Direct Cost: ¥9,400,000、Indirect Cost: ¥2,820,000)
Fiscal Year 2018: ¥12,220,000 (Direct Cost: ¥9,400,000、Indirect Cost: ¥2,820,000)
Fiscal Year 2017: ¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000)
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| Outline of Final Research Achievements |
In various stromal cells (fibroblasts, mesenchymal progenitor cells, and adipocytes), conditioned medium obtained from cultured osteosarcoma cells enhanced the activation of megakaryoblastic leukemia 1 (MKL1) which is a transcriptional regulator as well as induced the transition of these cells to cancer-associated fibroblasts (CAFs). We induced expression of MKL1 in various stromal cells and found that they increased expression of CAF-related genes and acquired CAF phenotypes. We also found that the interaction with serum response factor (SRF) is required for MKL1-induced CAF differentiation. In addition, we found that Rho-kinase inhibitor fasudil prevented nuclear translocation of MKL1 via actin dynamics and suppressed CAF differentiation as well as tumor formation in mouse osteosarcoma model. These findings suggest that MKL1 is a master regulator of the transition of stromal cells to CAFs and blocking CAF differentiation may provide a novel therapeutic approach for cancers.
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