RESUMEN

Hepatocellular carcinoma (HCC) is a disease of high unmet medical need that has become a global health problem. The development of targeted therapies for HCC has been hindered by the incomplete understanding of HCC pathogenesis and the limited number of relevant preclinical animal models. We recently unveiled a previously uncharacterized YES kinase (encoded by YES1)-dependent oncogenic signaling pathway in HCC. To model this subset of HCC, we established a series of syngeneic cell lines from liver tumors of transgenic mice expressing activated human YES. The resulting cell lines (referred to as HepYF) were enriched for expression of stem cell and progenitor markers, proliferated rapidly, and were characterized by high SRC family kinase (SFK) activity and activated mitogenic signaling pathways. Transcriptomic analysis indicated that HepYF cells are representative of the most aggressive proliferation class G3 subgroup of HCC. HepYF cells formed rapidly growing metastatic tumors upon orthotopic implantation into syngeneic hosts. Treatment with sorafenib or the SFK inhibitor dasatinib markedly inhibited the growth of HepYF tumors. The new HepYF HCC cell lines provide relevant preclinical models to study the pathogenesis of HCC and test novel small-molecule inhibitor and immunotherapy approaches.

Asunto(s)

Carcinoma Hepatocelular , Proliferación Celular , Modelos Animales de Enfermedad , Neoplasias Hepáticas , Metástasis de la Neoplasia , Animales , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Proliferación Celular/efectos de los fármacos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Humanos , Línea Celular Tumoral , Sorafenib/farmacología , Sorafenib/uso terapéutico , Dasatinib/farmacología , Dasatinib/uso terapéutico , Ratones Transgénicos , Ratones , Familia-src Quinasas/metabolismo , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Transducción de Señal/efectos de los fármacos , Niacinamida/análogos & derivados , Niacinamida/farmacología

RESUMEN

Most of our understanding regarding the involvement of SRC-family tyrosine kinases in cancer has stemmed from studies focused on the prototypical SRC oncogene. However, emerging research has shed light on the important role of YES signaling in oncogenic transformation, tumor growth, metastatic progression, and resistance to various cancer therapies. Clinical evidence indicates that dysregulated expression or activity of YES is a frequent occurrence in human cancers and is associated with unfavorable outcomes. These findings provide a compelling rationale for specifically targeting YES in certain cancer subtypes. Here, we review the crucial role of YES in cancer and discuss the challenges associated with translating preclinical observations into effective YES-targeted therapies.

Asunto(s)

Neoplasias , Proteínas Proto-Oncogénicas , Humanos , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-yes , Proteínas Tirosina Quinasas/metabolismo , Familia-src Quinasas/genética , Familia-src Quinasas/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/genética

RESUMEN

Identification of dominant, actionable oncogenic signaling pathways is key to guide the development of new targeted treatments for advanced-stage hepatocellular carcinoma (HCC). We have recently unveiled a novel YES-YAP/TAZ signaling axis involved in liver cancer development. Our study identifies the tyrosine kinase YES as a potential therapeutic target in HCC.

RESUMEN

Most patients with hepatocellular carcinoma (HCC) are diagnosed at a late stage and have few therapeutic options and a poor prognosis. This is due to the lack of clearly defined underlying mechanisms or a dominant oncogene that can be targeted pharmacologically, unlike in other cancer types. Here, we report the identification of a previously uncharacterized oncogenic signaling pathway in HCC that is mediated by the tyrosine kinase Yes. Using genetic and pharmacological interventions in cellular and mouse models of HCC, we showed that Yes activity was necessary for HCC cell proliferation. Transgenic expression of activated Yes in mouse hepatocytes was sufficient to induce liver tumorigenesis. Yes phosphorylated the transcriptional coactivators YAP and TAZ (YAP/TAZ), promoting their nuclear accumulation and transcriptional activity in HCC cells and liver tumors. We also showed that YAP/TAZ were effectors of the Yes-dependent oncogenic transformation of hepatocytes. Src family kinase activation correlated with the tyrosine phosphorylation and nuclear localization of YAP in human HCC and was associated with increased tumor burden in mice. Specifically, high Yes activity predicted shorter overall survival in patients with HCC. Thus, our findings identify Yes as a potential therapeutic target in HCC.

Asunto(s)

Carcinoma Hepatocelular , Neoplasias Hepáticas , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Humanos , Neoplasias Hepáticas/metabolismo , Ratones , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Transducción de Señal , Proteínas Señalizadoras YAP

RESUMEN

Defective Hippo/YAP signaling in the liver results in tissue overgrowth and development of hepatocellular carcinoma (HCC). Here, we uncover mechanisms of YAP-mediated hepatocyte reprogramming and HCC pathogenesis. YAP functions as a rheostat in maintaining metabolic specialization, differentiation, and quiescence within the hepatocyte compartment. Increased or decreased YAP activity reprograms subsets of hepatocytes to different fates associated with deregulation of the HNF4A, CTNNB1, and E2F transcriptional programs that control hepatocyte quiescence and differentiation. Importantly, treatment with small interfering RNA-lipid nanoparticles (siRNA-LNPs) targeting YAP restores hepatocyte differentiation and causes pronounced tumor regression in a genetically engineered mouse HCC model. Furthermore, YAP targets are enriched in an aggressive human HCC subtype characterized by a proliferative signature and absence of CTNNB1 mutations. Thus, our work reveals Hippo signaling as a key regulator of the positional identity of hepatocytes, supports targeting of YAP using siRNA-LNPs as a paradigm of differentiation-based therapy, and identifies an HCC subtype that is potentially responsive to this approach.