HUMAN FIBROLAMELLAR HEPATOCELLULAR CARCINOMAS (hFL-HCCS)

Abstract

The present disclosure provides a model of human fibrolamellar hepatocellular carcinoma (FL-HCC) cells maintained as a transplantable tumor line in a host and a method to establish a transplantable human FL-HCC tumor line. Methods of ex vivo cultures of the FL-HCC are provided. Methods of diagnosing and treating FL-HCC tumors are also provided.

What is claimed is: 
     
         1 . A transplantable tumor line of human fibrolamellar hepatocellular carcinoma (hFL-HCC) cells maintained in a non-human animal. 
     
     
         2 . The transplantable tumor line of  claim 1 , wherein the non-human animal is a NOD scid gamma (NSG) mouse. 
     
     
         3 . The transplantable tumor line of  claim 1 , wherein the hFL-HCC cells are derived from a tumor removed from the liver, from the biliary tree, from a subcutaneous tumor or from an intraperitoneal (ascites) tumor. 
     
     
         4 . The transplantable tumor line of  claim 1 , wherein the tumor line comprises hFL-HCC cells and mesenchymal cells of the non-human animal. 
     
     
         5 . The transplantable tumor line of  claim 1 , wherein at least 50% of the hFL-HCC cells in the transplantable tumor are cancer stem cells. 
     
     
         6 . The transplantable tumor line of  claim 1 , wherein the hFL-HCC cells express the fusion transcript DNAJB1-PRKACA. 
     
     
         7 . The transplantable tumor line of  claim 1 , wherein the hFL-HCC cells overexpress at least one C10orf128, CA12, CREB3L1, GALNTL6, IRF4, ITPRIP, KCNE4, NOVA1, OAT, PAK3, PCSK1, PHACTR2, RPS6KA2, SLC16A14, TMEM163, or TNRC6C relative to a control sample. 
     
     
         8 . The transplantable tumor line of  claim 7 , wherein the control sample is selected from the group consisting of hepatocellular carcinomas (HCCs), hepatoblastomas, cholangiocarcinomas (CCAs), pancreatic cancer, biliary tree stem cells, hepatic stem cells, hepatoblasts, pancreatic stem cells, hepatic, pancreatic committed progenitors, and normal mature hepatic or pancreatic cells. 
     
     
         9 . A tissue sample obtained from the tumor line of  claim 1 . 
     
     
         10 . A population of hFL-HCC cells isolated from the tumor line of  claim 1 . 
     
     
         11 . The population of  claim 10 , wherein the hFL-HCC cells are cultured on tissue culture plastic or on or in hyaluronans. 
     
     
         12 . The composition of  claim 11 , wherein the hFL-HCC cells are cultured in cells in serum-free medium. 
     
     
         13 . The composition of  claim 12 , wherein the serum-free medium is Kubota's Medium. 
     
     
         14 . The composition of  claim 12 , wherein the serum-free medium further contains hyaluronans, HGF and/or VEGF. 
     
     
         15 . A method of determining whether a patient has fibrolamellar hepatocellular carcinoma (FL-HCC), comprising: (a) measuring gene expression levels of at least one of C10orf128, CA12, CREB3L1, GALNTL6, IRF4, ITPRIP, KCNE4, NOVA1, OAT, PAK3, PCSK1, PHACTR2, RPS6KA2, SLC16A14, TMEM163, and TNRC6C; and (b) comparing the gene expression profile to one or more control samples. 
     
     
         16 . The method of  claim 15 , wherein overexpression of C10orf128, CA12, CREB3L1, GALNTL6, IRF4, ITPRIP, KCNE4, NOVA1, OAT, PAK3, PCSK1, PHACTR2, RPS6KA2, SLC16A14, TMEM163 or TNRC6C relative to the control sample is associated with presence of FL-HCC. 
     
     
         17 . The method of  claim 16 , wherein overexpression of PCSK1, CA12, NOVA1, SLC16A14, TNRC6C, TMEM163, and RPS6KA2 relative to the control sample is associated with presence of FL-HCC. 
     
     
         18 . The method of  claim 16 , wherein overexpression of C10orf128, OAT, PAK3, PCSK1, PHACTR2, SLC16A14, TMEM163, and TNRC6C relative to the control sample is associated with presence of FL-HCC. 
     
     
         19 . The method of  claim 15 , wherein the control sample is selected from the tumor cells from hepatocellular carcinomas (HCCs), hepatoblastomas, cholangiocarcinomas (CCAs) and/or pancreatic cancers or selected from normal cells consisting of biliary tree stem cells, hepatic stem cells, hepatoblasts, pancreatic stem cells, hepatic or pancreatic committed progenitors, and normal mature hepatic or pancreatic cells. 
     
     
         20 . A method of treating a patient determined to have hFL-HCC by administering to the patient an effective amount of at least one therapeutic that decreases expression of at least one of C10orf128, CA12, CREB3L1, GALNTL6, IRF4, ITPRIP, KCNE4, NOVA1, OAT, PAK3, PCSK1, PHACTR2, RPS6KA2, SLC16A14, TMEM163, or TNRC6C. 
     
     
         21 . The method of  claim 20 , wherein the at least one therapeutic is selected from the group consisting of a small molecule, RNA interference, a locked nucleic acid (LNA), an immunotherapy, a hedgehog signaling inhibitor, a histone deacetylase inhibitor, a protein kinase inhibitor, and a regulator of substrate targets of PRKACA. 
     
     
         22 . A method for drug screening, comprising (a) introducing a candidate drug to cultured hFL-HCC cells that are in the form of monolayers, hydrogels, spheroids or organoids, and (b) monitoring the effect of the candidate drug on the cultured hFL-HCC cells. 
     
     
         23 . A transplantable tumor cell line comprising human fibrolamellar hepatocellular carcinoma (hFL-HCC) cells, which can be maintained in a non-human animal.