Syngeneic mouse model of YES-driven metastatic and proliferative hepatocellular carcinoma.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1054524 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27291418.fastq.gz | Fastqsanger.gz | |||
| SRR27291419.fastq.gz | Fastqsanger.gz | |||
| SRR27291420.fastq.gz | Fastqsanger.gz | |||
| SRR27291421.fastq.gz | Fastqsanger.gz | |||
| SRR27291422.fastq.gz | Fastqsanger.gz |
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Project description: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 have recently unveiled a novel YES-dependent oncogenic signaling pathway in HCC. To model this subset of HCC, we have established a series of syngeneic cell lines from liver tumors of transgenic mice expressing activated YES. The resulting HepYF cell lines were enriched for expression of stem cell/progenitor markers, proliferated rapidly and were characterized by high SRC-family kinase 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.
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Project description:Hepatocellular carcinoma (HCC) is a disease with high unmet medical need. Most patients are diagnosed at late stage with few therapeutic options and a dismal prognosis. While molecular genomic studies have been helpful in improving the understanding and treatment of many types of cancer, their impact on HCC has been negligible so far. This is largely due to a poor understanding of the underlying mechanisms of this cancer and the lack of dominant oncogene that can be targeted pharmacologically. Here we report the identification of a novel Yes oncogenic signaling pathway in HCC that has escaped large-scale molecular genetic studies. Using a combination of genetic and pharmacological interventions in cellular and mouse models of HCC, we show that Yes activity is necessary for HCC cell proliferation. Transgenic expression of activated Yes in mouse hepatocytes is sufficient to induce liver tumorigenesis. Mechanistically, we found that Yes directly phosphorylates YAP and TAZ, promoting their nuclear accumulation and transcriptional activity in HCC cells and liver tumors, and that YAP/TAZ are effectors of Yes oncogenic transformation. Src-family kinase activation correlates with YAP tyrosine phosphorylation and nuclear localization in human HCC, and is associated with increased tumor burden. Specifically, high Yes activity predicts significantly shorter overall survival in HCC patients. Our findings identify Yes as a potential therapeutic target in HCC.
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Project description:Hepatocellular carcinoma (HCC) is a disease with high unmet medical need. Most patients are diagnosed at late stage with few therapeutic options and a dismal prognosis. While molecular genomic studies have been helpful in improving the understanding and treatment of many types of cancer, their impact on HCC has been negligible so far. This is largely due to a poor understanding of the underlying mechanisms of this cancer and the lack of dominant oncogene that can be targeted pharmacologically. Here we report the identification of a novel Yes oncogenic signaling pathway in HCC that has escaped large-scale molecular genetic studies. Using a combination of genetic and pharmacological interventions in cellular and mouse models of HCC, we show that Yes activity is necessary for HCC cell proliferation. Transgenic expression of activated Yes in mouse hepatocytes is sufficient to induce liver tumorigenesis. Mechanistically, we found that Yes directly phosphorylates YAP and TAZ, promoting their nuclear accumulation and transcriptional activity in HCC cells and liver tumors, and that YAP/TAZ are effectors of Yes oncogenic transformation. Src-family kinase activation correlates with YAP tyrosine phosphorylation and nuclear localization in human HCC, and is associated with increased tumor burden. Specifically, high Yes activity predicts significantly shorter overall survival in HCC patients. Our findings identify Yes as a potential therapeutic target in HCC.
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Project description:Hepatocellular carcinoma (HCC) is a disease with high unmet medical need. Most patients are diagnosed at late stage with few therapeutic options and a dismal prognosis. While molecular genomic studies have been helpful in improving the understanding and treatment of many types of cancer, their impact on HCC has been negligible so far. This is largely due to a poor understanding of the underlying mechanisms of this cancer and the lack of dominant oncogene that can be targeted pharmacologically. Here we report the identification of a novel Yes oncogenic signaling pathway in HCC that has escaped large-scale molecular genetic studies. Using a combination of genetic and pharmacological interventions in cellular and mouse models of HCC, we show that Yes activity is necessary for HCC cell proliferation. Transgenic expression of activated Yes in mouse hepatocytes is sufficient to induce liver tumorigenesis. Mechanistically, we found that Yes directly phosphorylates YAP and TAZ, promoting their nuclear accumulation and transcriptional activity in HCC cells and liver tumors, and that YAP/TAZ are effectors of Yes oncogenic transformation. Src-family kinase activation correlates with YAP tyrosine phosphorylation and nuclear localization in human HCC, and is associated with increased tumor burden. Specifically, high Yes activity predicts significantly shorter overall survival in HCC patients. Our findings identify Yes as a potential therapeutic target in HCC.
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Project description:Hepatocellular carcinoma (HCC) is a disease with high unmet medical need. Most patients are diagnosed at late stage with few therapeutic options and a dismal prognosis. While molecular genomic studies have been helpful in improving the understanding and treatment of many types of cancer, their impact on HCC has been negligible so far. This is largely due to a poor understanding of the underlying mechanisms of this cancer and the lack of dominant oncogene that can be targeted pharmacologically. Here we report the identification of a novel Yes oncogenic signaling pathway in HCC that has escaped large-scale molecular genetic studies. Using a combination of genetic and pharmacological interventions in cellular and mouse models of HCC, we show that Yes activity is necessary for HCC cell proliferation. Transgenic expression of activated Yes in mouse hepatocytes is sufficient to induce liver tumorigenesis. Mechanistically, we found that Yes directly phosphorylates YAP and TAZ, promoting their nuclear accumulation and transcriptional activity in HCC cells and liver tumors, and that YAP/TAZ are effectors of Yes oncogenic transformation. Src-family kinase activation correlates with YAP tyrosine phosphorylation and nuclear localization in human HCC, and is associated with increased tumor burden. Specifically, high Yes activity predicts significantly shorter overall survival in HCC patients. Our findings identify Yes as a potential therapeutic target in HCC.
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Project description:The biologic basis for NSCLC metastasis is not well understood. Here we addressed this deficiency by transcriptionally profiling tumors from a genetic mouse model of human lung adenocarcinoma that develops metastatic disease owing to the expression of K-rasG12D and p53R172H. As a tool to investigate the biologic basis for metastasis in this model and to query the roles of specific genes in this signature, we isolated adenocarcinoma cell lines from these mice and used them to develop a syngeneic tumor model in wild-type littermates. Transcriptional profiling of the highly metastatic subcutaneous tumors revealed genes that regulate, among other processes, epithelial-to-mesenchymal transition and intra-tumoral inflammation and angiogenesis, whereas the non-metastatic tumors did not. Experiment Overall Design: Cell lines from p53R172Hâg/+ K-rasLA1/+ mice were derived from tumor tissues removed at autopsy from two different mice (#344 and #393). The tissues were minced, placed in culture, and passed serially in RPMI 1640 supplemented with 10% fetal bovine serum (FBS), which yielded mass populations of tumor cells derived from primary lung tumors (344P and 393P), mediastinal lymph nodes (344LN and 393LN), and a subcutaneous site (344SQ). Syngeneic tumors were isolated, carefully dissected to remove the adjacent tissue, snap-frozen in liquid nitrogen and stored at -80° until use. Part of each dissected tumor was histologically evaluated by a board-certified pathologist. Snap-frozen samples were processed and analyzed on Affymetrix Mouse Expression Array 430A 2.0 chips. Experiment Overall Design: Expression profiling performed on 344SQ, 393P, and 393LN
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