PET imaging phenotypic difference between primary and metastatic tumors. A, The generation of the KrasG12D/+ Trp53fl/fl Rosa26N1icd/+ (KPN) and KPN liver metastasis organoid lines and subsequent implantation. One pair of lines, generated from a matched mouse primary tumor and liver metastasis, which were then propagated and injected subcutaneously into recipient mice (n = 5). B, Transverse and coronal PET/MRI slice images showing uptake of four PET tracers ([18F]FDG, [18F]FET, [18F]FLT, [18F]ACE) in subcutaneously implanted KPN primary and KPN liver metastasis organoids. KPN primary tumor-bearing mice are the same four PET ([18F]FDG, [18F]FET, [18F]FLT, [18F]ACE) images (primary) as displayed in Figs. 2B and 4B and D. C, Standard uptake peak values (SUVpeak) PET quantification from images in B. Sample size (n) is displayed on the bars. Error bars represent SD. Data compared using unpaired t test. Details of all mice used in these studies are presented in Supplementary Table S1. D, Representative GLUT-1 IHC and Lat-1/Slc7a5 ISH. Black scale bars represent 50 μm (*, P < 0.05; ***, P < 0.001; see also Supplementary Fig. S8). (A, Created with BioRender.com.)
ARTICLE ABSTRACT
The current approach for molecular subtyping of colon cancer relies on gene expression profiling, which is invasive and has limited ability to reveal dynamics and spatial heterogeneity. Molecular imaging techniques, such as PET, present a noninvasive alternative for visualizing biological information from tumors. However, the factors influencing PET imaging phenotype, the suitable PET radiotracers for differentiating tumor subtypes, and the relationship between PET phenotypes and tumor genotype or gene expression–based subtyping remain unknown.
In this study, we conducted 126 PET scans using four different metabolic PET tracers, [18F]fluorodeoxy-D-glucose ([18F]FDG), O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET), 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT), and [11C]acetate ([11C]ACE), using a spectrum of five preclinical colon cancer models with varying genetics (BMT, AKPN, AK, AKPT, KPN), at three sites (subcutaneous, orthograft, autochthonous) and at two tumor stages (primary vs. metastatic).
The results demonstrate that imaging signatures are influenced by genotype, tumor environment, and stage. PET imaging signatures exhibited significant heterogeneity, with each cancer model displaying distinct radiotracer profiles. Oncogenic Kras and Apc loss showed the most distinctive imaging features, with [18F]FLT and [18F]FET being particularly effective, respectively. The tissue environment notably impacted [18F]FDG uptake, and in a metastatic model, [18F]FET demonstrated higher uptake.
By examining factors contributing to PET-imaging phenotype, this study establishes the feasibility of noninvasive molecular stratification using multiplex radiotracer PET. It lays the foundation for further exploration of PET-based subtyping in human cancer, thereby facilitating noninvasive molecular diagnosis.
