Cancer as a Model System for Testing Metabolic Scaling Theory

Abstract

Biological allometries, such as the scaling of metabolism to mass, are hypothesized to result from natural selection to maximize how vascular networks fill space yet minimize internal transport distances and resistance to blood flow. Metabolic scaling theory argues two guiding principles—conservation of fluid flow and space-filling fractal distributions—describe a diversity of biological networks and predict how the geometry of these networks influences organismal metabolism. Yet, mostly absent from past efforts are studies that directly, and independently, measure metabolic rate from respiration and vascular architecture for the same organ, organism, or tissue. Lack of these measures may lead to inconsistent results and conclusions about metabolism, growth, and allometric scaling. We present simultaneous and consistent measurements of metabolic scaling exponents from clinical images of lung cancer, serving as a first-of-its-kind test of metabolic scaling theory, and identifying potential quantitative imaging biomarkers indicative of tumor growth. We analyze data for 535 clinical PET-CT scans of patients with non-small cell lung carcinoma to establish the presence of metabolic scaling between tumor metabolism and tumor volume. Furthermore, we use computer vision and mathematical modeling to examine predictions of metabolic scaling based on the branching geometry of the tumor-supplying blood vessel networks in a subset of 56 patients diagnosed with stage II-IV lung cancer. Examination of the scaling of maximum standard uptake value with metabolic tumor volume, and metabolic tumor volume with gross tumor volume, yield metabolic scaling exponents of 0.64 (0.20) and 0.70 (0.17), respectively. We compare these to the value of 0.85 (0.06) derived from the geometric scaling of the tumor-supplying vasculature. These results: (1) inform energetic models of growth and development for tumor forecasting; (2) identify imaging biomarkers in vascular geometry related to blood volume and flow; and (3) highlight unique opportunities to develop and test the metabolic scaling theory of ecology in tumors transitioning from avascular to vascular geometries.

Neuronal branching is increasingly asymmetric near synapses, potentially enabling plasticity while minimizing energy dissipation and conduction time

“…Although length asymmetry might provide additional insights into the properties of these networks, the branch length measurements are not accurately characterized, as also previously reported for vascular scaling [ 30 ] as well as other types of plant and animal networks [ 31 , 32 ]. Recent work suggests Horton–Strahler labelling—where the first level begins at the tips, and higher levels are determined when two branches of the same level combine—may yield better estimates of branch length scaling, as it has been previously applied to neurons and other biological networks [ 66 – 68 ]. In future work, we plan to investigate how this alternative labelling scheme for branch lengths compares with theoretical predictions derived using our framework.…”

How axon and dendrite branching are guided by time, energy, and spatial constraints

“…We have have chosen to focus on radius scaling ratios in this analysis because the branch length measurements are not accurately characterized, as also previously reported for vascular scaling 57 . Recent work suggests Horton-Strahler labeling—where the first level begins at the tips, and higher levels are determined when two branches of the same level combine—may yield better estimates of branch length scaling 69 . For instance, previous work on river networks has used Horton–Strahler labeling, and it has been applied to other networks in biology, particularly those in in which asymmetric branching is observed 70 , 71 .…”

Ploidy modulates cell size and metabolic rate inXenopusembryos

“…At the single-cell level, research on experimentally induced polyploid yeast ( 6 ) or animal cells ( 8 ), as well as enlarged animal cells ( 9 – 11 ) is beginning to unravel unexpected connections among ploidy, cell size, fitness, and metabolism ( 12 ) but has not yet revealed consequences for tissues. For example, while numerous studies have investigated metabolic shifts and allometric relationships in cancer ( 13 ), how changes in cell size and ploidy, both hallmarks of tumorigenesis ( 14 ), alter tumor metabolism remains poorly understood. Importantly, species comparisons have demonstrated a negative association between genome size and developmental rate in amphibians ( 15 ), as well as a more debated negative correlation with metabolic rate in adult birds and amphibians ( 16 , 17 ), suggesting that genome size is connected to whole-organism physiology.…”

“…Thus, the ratio of cell surface area to volume is one factor contributing to whole organism metabolism in vertebrates. While there have been recent advances in theories of metabolic scaling ( 39 ) and cellular energetics ( 40 , 41 ), our work establishes a powerful and tractable system to bridge the gap between cell size-dependent energetics and organism metabolism ( 12 , 30 , 42 ) and address fundamental questions with respect to polyploid tissue metabolism ( 1 , 2 , 13 ), genome size evolution ( 43 ), and the embryo energy budget ( 26 , 29 ).…”