Sandholm, J. | bioRxiv Science

bioRxiv2024

Positron emission tomography (PET) tracer enables imaging of high CD73 expression in cancer

Ecto-5-nucleotidase (CD73) is a potential new drug target for cancer immunotherapy. Its overexpression is associated with various aggressive cancers, including triple-negative breast cancer (TNBC) and pancreatic cancer, making it a promising target for diagnostic imaging. Besides antibodies, small molecule CD73 inhibitors have been developed and are currently in clinical trials. This study aimed to develop and evaluate fluorine-18 labeled high-affinity CD73 inhibitors as tracers for the non-invasive positron emission tomography (PET) imaging of CD73 expression in cancer. Two CD73 inhibitors were selected for radiolabeling based on their high potency (Ki values of ca. 1 nM), and favorable pharmacokinetic properties providing [18F]PSB-19427 ([18F]1) and [18F]MRS-4648 ([18F]2). Ex vivo imaging studies on human breast cancer tissues indicated specific binding of both radiotracers. Subsequent in vivo studies proved [18F]1 to be superior due to its long elimination half-life and its accumulation in TNBC and pancreatic cancer tissues, suggesting its potential as a versatile PET tracer for imaging various solid tumors. [18F]1 significantly outperformed [18F]FDG in visualizing triple-negative breast cancer, offering potential advantages over [18F]FDG in terms of specificity and diagnostic accuracy. Thus, [18F]1 is a PET tracer with outstanding properties suitable for broad application in cancer diagnosis and potentially in therapy control. Based on these results, further clinical development of PET tracers targeting CD73 is warranted. One Sentence SummaryA PET tracer for imaging CD73 expression was developed, enabling cancer diagnosis.

cancer biology↗

bioRxiv2019

Growth Mode and Carbon Source Impact the Surfaceome Dynamics of Lactobacillus rhamnosus GG

Bacterial biofilms have clear implications in disease and in food applications involving probiotics. Here, we show that switching the carbohydrate source from glucose to fructose increased the biofilm formation and the total surface-antigenicity of a well-known probiotic, Lactobacillus rhamnosus GG. Surfaceomes (all cell surface-associated proteins) of GG cells grown with glucose and fructose in planktonic and biofilm cultures were identified and compared, which indicated carbohydrate source-dependent variations, especially during biofilm growth. The most distinctive differences under these conditions were detected with several surface adhesins (e.g., MBF, SpaC/A pilus and penicillin-binding proteins), enzymes (glycoside hydrolases, PrsA, PrtP, PrtR and HtrA) and moonlighting proteins (glycolytic, transcription/translation and stress-associated proteins, r-proteins, tRNA synthetases, Clp family proteins, PepC, PepN and PepA). The abundance of several known adhesins and novel moonlighters, including enzymes acting on casein-derived peptides (ClpP, PepC and PepN), increased in the biofilm cells grown on fructose, from which the surface-associated aminopeptidase activity mediated by PepC and PepN was further confirmed by an enzymatic assay. The classical surface adhesins were predicted to be more abundant on planktonic cells growing either on fructose (MBF and SpaA) or glucose (SpaC). An additional indirect ELISA indicated both growth mode- and carbohydrate-dependent differences in abundance of SpaC, whereas the overall adherence of GG assessed with porcine mucus indicated that the carbon source and the growth mode affected mucus adhesion. The adherence of GG cells to mucus was almost completely inhibited by anti-SpaC antibodies regardless of growth mode and/or carbohydrate source, indicating the key role of the SpaCBA pilus in adherence under the tested conditions. Altogether, our results suggest that carbon source and growth mode coordinate classical and nonclassical protein export in GG, which ensures the presence of an integral and coordinated system that contributes to resistance, nutrient acquisition and cell-cell interactions under different conditions. In conclusion, the present study shows that different growth regimes and conditions can have a profound impact on the adherent and antigenic features of GG, thereby providing new information on how to gain additional benefits from this probiotic.

microbiology↗