Longitudinal multi-tracer imaging of hepatocellular carcinoma identifies novel stage- and oncogene-specific changes

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths, globally. There is a need for novel biomarkers for early detection and novel, effective targeted therapies. Molecular imaging can faithfully visualize, characterize and quantify specific relevant biological processes.

We performed longitudinal dedicated small-animal positron emission tomography-computed tomography (PET/CT) imaging to analyze changes in glucose metabolism using [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG), amino acid turnover with [¹⁸F]fluoroethyltyrosine ([¹⁸F]FET), and chemokine receptor expression using [⁶⁸Ga]pentixafor targeting CXCR4, during stages of early tumor development, overt HCC and regression. We used two conditional transgenic mouse models of HCC, driven by clinically relevant oncogenes c-MYC (LT2/MYC) or HRASV12 (LT2/RAS). Conditional doxycycline-regulated mouse models, enable liver-specific oncogene activation or inhibition, leading to liver tumor development and regression, respectively. Correlation of our PET/CT findings with our gene expression and metabolomics data and with histological analyses followed.

We show PET/CT identifies HCC stage-specific and oncogene-specific molecular changes that may serve as potential novel biomarkers and therapeutic targets. Glucose metabolism and CXCR4 chemokine expression are differentially deregulated during HCC development in an oncogene-specific manner. Our [¹⁸F]FDG results correlated with glucose transporter GLUT1 gene expression and with our metabolomics data. Increased expression of CXCR4 and CD68 inflammatory markers mirrored [⁶⁸Ga]pentixafor results in LT2/MYC mice. FET-based measurement of amino acid turnover are insensitive to stages of HCC-development, in our studies. Concurrently, no significant changes in expression of tyrosine metabolism genes were observed.

Our study highlights that identified changes in targeted molecular imaging can facilitate a better understanding of underlying biological processes and may help guide novel oncogene-specific targeted anti-tumor therapies in HCC, with promising translational potential.