Abstract
Τhe morphology, physiology and immunology, of solid tumors exhibit spatial heterogeneity which complicates our understanding of cancer progression and therapy response. Understanding spatial heterogeneity necessitates high resolution in vivo imaging of anatomical and pathophysiological tumor information. We introduce Rhodobacter as bacterial reporter for multispectral optoacoustic (photoacoustic) tomography (MSOT). We show that endogenous bacteriochlorophyll a in Rhodobacter gives rise to strong optoacoustic signals >800 nm away from interfering endogenous absorbers. Importantly, our results suggest that changes in the spectral signature of Rhodobacter which depend on macrophage activity inside the tumor can be used to reveal heterogeneity of the tumor microenvironment. Employing non-invasive high resolution MSOT in longitudinal studies we show spatiotemporal changes of Rhodobacter spectral profiles in mice bearing 4T1 and CT26.WT tumor models. Accessibility of Rhodobacter to genetic modification and thus to sensory and therapeutic functions suggests potential for a theranostic platform organism.
Highlights
Τhe morphology, physiology and immunology, of solid tumors exhibit spatial heterogeneity which complicates our understanding of cancer progression and therapy response
In addition to Rba. sphaeroides ATH 2.4.1, which could successfully be used for tumor targeting and visualization by detecting bacteriochlorophyll a (BChl a)-dependent fluorescence[22], we analyzed the nonsulfur purple bacteria strains Rba. capsulatus SB1003 and B10S as well as the SB1003 mutant strain ΔcrtJ carrying a deletion within the repressor gene involved in O2-mediated inhibition of BChl a biosynthesis[26]
Our results clearly link the change of the spectral signature to macrophage activity in different regions of the tissue, which is an important contribution to understanding the tumor microenvironment and the spatially and temporally diverse plasticity, activity and overall functionality of macrophages[33], especially, since M2-like tumor-associated macrophages (TAM) are critical for shaping this microenvironment[34]
Summary
Physiology and immunology, of solid tumors exhibit spatial heterogeneity which complicates our understanding of cancer progression and therapy response. Magnetic resonance imaging (MRI)[7], X-ray, computer tomography (CT), or ultrasonography enable high-resolution visualization of morphology and functional tumor parameters, but detailed sensing of pathophysiological parameters over time is challenging due to the limited sensitivity afforded Techniques such as PET or MRI require large infrastructure out of the reach of many research institutions. We consider facultative phototrophic purple bacteria that are intrinsically rich in bacteriochlorophyll a (BChl a), which exhibits several favorable characteristics as OA labels: two clearly defined spectral bands in the near-infrared range (λmax of 800 and ~860 nm) with high molar absorptivity[20,21] which are red-shifted compared to all genetically encoded labels reported for OA so far, suggesting a unique potential for clear differentiation of bacterial signal from endogenous absorbers prevalent in tissue such as blood hemoglobin and lipids. We investigate the suitability of different Rhodobacter species for optoacoustic signal generation, explore their fate after intratumoral injection and the potential of their distinct spectral signature to carry any additional information from the tumor microenvironment
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