한빛사 논문
Kyungjoo Cho1,2,¶, Simon Weonsang Ro3,¶, Hye Won Lee2,4, Hyuk Moon3, Sojung Han2,4, Hye Rim Kim5, Sang Hoon Ahn2,4, Jun Yong Park1,2,4,*, and Do Young Kim2,4,*
1Brain Korea 21 Project for Medical Science College of Medicine, Yonsei University, Seoul
03722, Korea
2Yonsei Liver Center, Yonsei University College of Medicine, Seoul 03722, Korea
3Department of Genetics and Biotechnology, College of Life Sciences, Kyung Hee University,
Yongin-si, Gyeonggi-do 17104, Korea
4Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 03722, Korea
5Biostatistics Collaboration Unit, Department of Biomedical Systems Informatics, Yonsei
University College of Medicine, Seoul 03722, Korea
¶These authors contributed equally to this work.
*To whom correspondence should be addressed Jun Yong Park, M.D., Ph.D., Do Young Kim, M.D., Ph.D.
Abstract
Backgroud & Aims
Hepatocellular carcinoma (HCC) is the most predominant type of liver cancer affecting 800,000 people globally each year. Various small-molecule compounds targeting diverse oncogenic signaling pathways have been tested for HCC patients and clinical outcomes were not satisfactory. In this study, we investigated molecular signaling that determines the efficiency of drug delivery into HCC.
Approach & Results
Hydrodynamics-based transfection (HT) was performed to develop mouse models for HCC induced by various oncogenes. Mice bearing liver cancer were treated with verteporfin at 5 weeks post HT. Multi-cellular HCC organoid (MCHO) models were established which contained various types of stromal cells, such as hepatic stellate cells, fibroblasts, and endothelial cells together with HCC cells. Tumor organoids were treated with verteporfin and distributions of the drug in the organoids were assessed using fluorescence microscopy. Murine HCC models developed by HT methods showed that a high YAP/TAZ activity in HCC cells impaired verteporfin penetration into the cancer. Activation of tumor stroma was observed in HCC with a high YAP/TAZ activity. Consistent with the findings in the in vivo models of HCC, MCHOs with activated YAP/TAZ signaling showed stromal activation and impaired penetration of verteporfin into the tumor organoids. Inhibition of YAP/TAZ transcriptional activity in HCC cells significantly increased drug penetration into the MCHO.
Conclusions
Drug delivery into liver cancer is impaired by YAP/TAZ signaling in tumor cells and subsequent activation of stroma by the signaling. Disrupting or targeting activated tumor stroma might improve drug delivery into HCC with an elevated YAP/TAZ activity.
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