1. Role of the c-Myc (Myc) oncoprotein in normal liver proliferation and metabolism. Myc is a bHLH-ZIP transcription factor that is among the first genes induced in response to growth factor stimulation or regenerative signals such as partial hepatectomy (PH). However, previous work has provided conflicting evidence as to Myc’s actual functional role in promoting hepatocyte proliferation following PH.  We reasoned that this inconsistency might be related to the relative short time over which hepatic regeneration occurs. Thus, we used a novel approach employing a model of hereditary tyrosinemia in which small numbers of myc+/+ or myc-/- hepatocytes are allowed to replace the disease liver parenchyma over a period exceeding 20 wks. Using either individual or mixed populations of these donor hepatocytes, we showed Myc to be unnecessary for the prolonged regenerative process afforded by this model system.  However myc-/-  hepatocytes both prior to and after transplantation showed evidence of neutral lipid accumulation reminiscent of NAFLD.  Taken together, these studies provided unequivocal evidence that Myc was unnecessary for normal hepatic regeneration but was necessary for maintaining a proper metabolic balance.

2. Role of a parallel, Myc-like pathway in normal liver proliferation and metabolism.  The bHLH-ZIP transcription factor ChREBP, is distantly related to Myc, is expressed at high levels in the liver and binds a subset of Myc target genes, particularly in response to metabolites such as glucose.  We hypothesized that the lack of requirement for Myc in normal hepatic regeneration described above may be due to ChREBP serving in a redundant capacity. Thus, current efforts are aimed at studying defects in hepatocytes proliferation or metabolism following the knockout of ChREBP or the double knockout involving ChREBP and Myc.

3. Mouse models of liver cancer. We are currently using two models of liver cancer to study the role of Myc.

a. Hepatocellular carcinoma (HCC). Rapid induction of aggressive and highly lethal HCCs occurs in response to hepatocyte-specific, tetracycline-regulatable induction of Myc.  Moreover, unlike regenerating normal hepatocytes, which are Myc-independent, HCCs are highly dependent on Myc’s continuous over-expression.  Indeed, rapid regression of tumors occurs following the silencing of Myc and recurrent tumors arise following Myc’s reinduction. This provides an excellent model for studying the secondary hits the drive HCCs in the face of Myc de-regulation and to study the order and context in which these changes arise.  We are using this model to study the evolution of primary and recurrent tumors with particular attention to the biochemical, transcriptional and metabolic changes associated  with these different phases

b. Hepatoblastoma. Tumors closely resembling pediatric hepatoblastomas (HBs) can be generated following the hydrodynamic tail vein injection of Sleeping Beauty vectors encoding mutant forms of beta-catenin and yes-associated protein (YAP), both of which are deregulated in the vast majority of human HBs. Similar to what is seen in many human HBs, these tumors tend to express very high levels of Myc. Using mice with a conditional, hepatocyte-specific knockout of Myc, we have shown that Myc is necessary for maximal tumor growth but not for initiation.  In depth molecular, biochemical and transcriptional profiling have shown this to be the result of the inability of the myc-/- HBs to maximally up-regulate genes involved in glycolysis, ribosomal biogenesis, fatty acid synthesis.  myc-/- HBs also have lower levels of acetyl-CoA and lack the ability to maximally acetylate and activate Myc target gene expression. These studies have also identified certain key proteins such as pyruvate dehydrogenase (PDH) as being potentially necessary to allow for optimal rates of tumor growth.  We are currently investigating this using pdh-/- mice to determine whether they  show reduced rates of tumor initiation and/or growth in response to beta-catenin + YAP over-expression.

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View Dr. Prochownik’s Report on nih.gov

View Dr. Prochownik’s publications on PubMed

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Professor of Microbiology & Molecular Genetics
Section of Hematology/Oncology

Team Leader, Tumorigenesis SIG