YAP/TAZ Suppress Drug Penetration Into Hepatocellular Carcinoma Through Stromal Activation

Abstract

BaCKgRoUND aND aIMS: 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 patients with HCC, and clinical outcomes were not satisfactory. In this study, we investigated molecular signaling that determines the efficiency of drug delivery into HCC.appRoaCH aND 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 after HT. Multicellular HCC organoid (MCHO) models were established that 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 Yes-associated protein/Transcriptional co-activator with PDZbinding motif (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. (Hepatology 2021;74:2605-2621).H CC is the most common type of liver cancer, accounting for about 80% of cases. The last decade has seen great advances in molecular targeted therapy for HCC. (1)(2)(3) Various small-molecule compounds targeting diverse oncogenic signaling pathways have been tested in preclinical and clinical settings. To date, however, clinical outcomes have been somewhat discouraging, as exemplified by sorafenib, the leading molecular target compound administered to patients with HCC. The mean survival benefit for sorafenib-treated groups compared with placebo groups is ~2-3 months. (4,5) Thus, development of target therapeutics is needed to improve treatment outcomes.The transcription factors YAP and its paralogue TAZ have attracted considerable recent attention in cancer research. (6,7) Studies have identified central roles for YAP/TAZ in tumor initiation and maintenance as well

YAP Dictates Mitochondrial Redox Homeostasis to Facilitate Obesity‐Associated Breast Cancer Progression

“…[ 26 ] Furthermore, activation of YAP/TAZ signaling was obligated to orchestrate tumor surrounding stromal cells. [ 27 ] These data suggest a possible role of YAP in governing obese‐associated TME. Thus, it is worth investigating the role of YAP/TAZ‐mediated metabolic remodeling in the crosstalk between breast tumors and the TME.…”

Animal Models of Hepatocellular Carcinoma: Current Applications in Clinical Research

“…Cho et al showed how specific oncogenic pathways, such as the yesassociated protein/transcriptional co-activator with PDZ-binding motif (YAP/TAZ) model, can lead to a constitutive 1274 activation of the stromal component impairing the penetration of treatments into the cancer tissue. 88 In fact, besides molecular dissection of mechanisms, animal models are pivotal for therapeutic approaches. Experimental tools include not only models mimicking different risk factors and molecular subgroups but also a wide range of tumor induction techniques, since the liver is highly receptive for any kind of molecules, including nucleic acids and viral vectors.…”

Tumor organoids: applications in cancer modeling and potentials in precision medicine

“…Both the tumor-suppressing or killing effects of drugs themselves and the efficient delivery of drugs into tumors are important for cancer treatment. Based on multicellular HCC organoids containing both HCC cells and diverse stromal cells (ECs, fibroblasts, and hepatic stellate cells) [181], high activity of Yes-associated protein/transcriptional coactivator with PDZ-binding motif signaling was shown to be associated with stromal activation in HCC and suppressed the penetration of verteporfin into tumoroids, indicating that treatments targeting activated cancer stroma might facilitate drug delivery into HCC [181].…”