Decoupling of metabolism and vasculature in tumors revealed by novel Capillary-Cell microscopy

A multidisciplinary team from Harvard Medical School, Duke University, and Massachusetts General Hospital has developed the dual-scale Capillary-Cell (CapCell) microscope, a revolutionary tool for visualizing tumor metabolism and vasculature dynamics. Published in BME Frontiers, this innovation addresses critical challenges in cancer treatment by quantifying spatial and temporal heterogeneity in tumor microenvironments.

Tumors are not uniform; they contain diverse regions with varying metabolic activities and blood supply. This heterogeneity is a major driver of treatment failure and recurrence. The newly developed CapCell microscope addresses this challenge by combining widefield imaging, which captures large-scale patterns across an entire tumor, with high-resolution imaging that zooms in on cellular and microregional features.

In this study, the team used the platform to monitor mouse models of breast cancer (4T1 tumors) before and after treatment with Combretastatin A-1 (CA1), a vascular-disrupting agent. The system tracked key metabolic indicators-mitochondrial membrane potential (using TMRE) and glucose uptake (using 2-NBDG)-alongside detailed maps of blood vessel density and distribution.

The findings uncovered a complex, dynamic relationship between a tumor's vascular network and its metabolic behavior. Immediately after the first CA1 treatment, both overall metabolism and vessel density dropped significantly. Intriguingly, within micro-regions, high mitochondrial activity was associated with areas of dense vasculature, while elevated glucose uptake was more common in poorly vascularized zones-highlighting distinct metabolic adaptations based on local conditions. A critical observation was that a second dose of CA1, administered days later, had minimal additional impact on tumor metabolism. By this later time point, metabolic activity had largely recovered to baseline levels, even though the vascular network remained sparse and did not regenerate correspondingly. This suggests a temporal decoupling between vascular supply and metabolic function. 

The CapCell system offers a 12-fold increase in optical power for high-resolution imaging by concentrating light into a specific field of view, significantly improving signal detection for faint metabolic fluorescence. Its relatively simple hardware also makes it adaptable for various laboratory and potentially clinical settings.

Looking ahead, the researchers plan to integrate additional probes to study lipid metabolism and the role of immune cells within the tumor microenvironment, further elucidating the complex ecological competition that fuels cancer progression and resistance.