Sequential adaptive changes in a c-Myc-driven model of hepatocellular carcinoma
James M Dolezal1, Huabo Wang1, Sucheta Kulkarni1
1From the Divisions of Hematology/Oncology and.
The Journal of Biological Chemistry
|April 23, 2017
Summary
This study reveals how c-Myc (Myc) drives hepatocellular carcinoma (HCC) by altering cell metabolism and gene expression. Recurrent HCC tumors can adapt and normalize some of these cancer-driving behaviors.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Hepatocellular carcinoma (HCC) is a prevalent cancer often linked to c-Myc (Myc) oncoprotein overexpression.
- Understanding the molecular and metabolic underpinnings of HCC progression and recurrence is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the metabolic, biochemical, and molecular alterations during the progression, regression, and recurrence of Myc-induced HCC in a mouse model.
- To identify how Myc influences cellular pathways and to characterize the adaptive changes in recurrent tumors.
Main Methods:
- Utilized a mouse model of Myc-induced HCC to track changes during tumor evolution.
- Performed metabolic and biochemical analyses, including pyruvate and fatty acid oxidation rates and mitochondrial function.
- Conducted RNA sequencing to analyze transcriptional changes in DNA repair, cell cycle, signaling pathways, immunity, and metabolism.
Main Results:
- Observed altered pyruvate and fatty acid metabolism, with glutamine potentially redirected to biosynthesis.
- Found reduced mitochondrial mass and altered electron transport chain contributions in initial tumors.
- RNA sequencing revealed dynamic transcriptional shifts related to DNA repair, cell cycle, IGF signaling, immunity, and metabolic reprogramming.
- Recurrent tumors exhibited "normalized" behaviors for a subset of deregulated functions compared to initial tumors.
Conclusions:
- Myc-driven HCC involves significant metabolic and transcriptional reprogramming.
- Recurrent HCC demonstrates adaptive plasticity, normalizing some oncogenic behaviors.
- These findings provide a comprehensive view of HCC evolution and recurrence, independent of therapeutic interventions.
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