Cancer cells depend on environmental lipids for proliferation when electron acceptors are limited.

Production of oxidized biomass, which requires regeneration of the cofactor NAD+, can be a proliferation bottleneck that is influenced by environmental conditions. However, a comprehensive quantitative understanding of metabolic processes that may be affected by NAD+ deficiency is currently missing. Here, we show that de novo lipid biosynthesis can impose a substantial NAD+ consumption cost in proliferating cancer cells. When electron acceptors are limited, environmental lipids become crucial for proliferation because NAD+ is required to generate precursors for fatty acid biosynthesis. We find that both oxidative and even net reductive pathways for lipogenic citrate synthesis are gated by reactions that depend on NAD+ availability. We also show that access to acetate can relieve lipid auxotrophy by bypassing the NAD+ consuming reactions. Gene expression analysis demonstrates that lipid biosynthesis strongly anti-correlates with expression of hypoxia markers across tumor types. Overall, our results define a requirement for oxidative metabolism to support biosynthetic reactions and provide a mechanistic explanation for cancer cell dependence on lipid uptake in electron acceptor-limited conditions, such as hypoxia.

Macroecological dynamics of gut microbiota.

The gut microbiota is now widely recognized as a dynamic ecosystem that plays an important role in health and disease. Although current sequencing technologies make it possible to explore how relative abundances of host-associated bacteria change over time, the biological processes governing microbial dynamics remain poorly understood. Therefore, as in other ecological systems, it is important to identify quantitative relationships describing various aspects of gut microbiota dynamics. In the present study, we use multiple high-resolution time series data obtained from humans and mice to demonstrate that, despite their inherent complexity, gut microbiota dynamics can be characterized by several robust scaling relationships. Interestingly, the observed patterns are highly similar to those previously identified across diverse ecological communities and economic systems, including the temporal fluctuations of animal and plant populations and the performance of publicly traded companies. Specifically, we find power-law relationships describing short- and long-term changes in gut microbiota abundances, species residence and return times, and the correlation between the mean and the temporal variance of species abundances. The observed scaling laws are altered in mice receiving different diets and are affected by context-specific perturbations in humans. We use the macroecological relationships to reveal specific bacterial taxa, the dynamics of which are substantially perturbed by dietary and environmental changes. Overall, our results suggest that a quantitative macroecological framework will be important for characterizing and understanding the complex dynamics of diverse microbial communities.

Quantifying spatiotemporal variability and noise in absolute microbiota abundances using replicate sampling.

Metagenomic sequencing has enabled detailed investigation of diverse microbial communities, but understanding their spatiotemporal variability remains an important challenge. Here, we present decomposition of variance using replicate sampling (DIVERS), a method based on replicate sampling and spike-in sequencing. The method quantifies the contributions of temporal dynamics, spatial sampling variability, and technical noise to the variances and covariances of absolute bacterial abundances. We applied DIVERS to investigate a high-resolution time series of the human gut microbiome and a spatial survey of a soil bacterial community in Manhattan's Central Park. Our analysis showed that in the gut, technical noise dominated the abundance variability for nearly half of the detected taxa. DIVERS also revealed substantial spatial heterogeneity of gut microbiota, and high temporal covariances of taxa within the Bacteroidetes phylum. In the soil community, spatial variability primarily contributed to abundance fluctuations at short time scales (weeks), while temporal variability dominated at longer time scales (several months).

Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers.

Tumor genetics guides patient selection for many new therapies, and cell culture studies have demonstrated that specific mutations can promote metabolic phenotypes. However, whether tissue context defines cancer dependence on specific metabolic pathways is unknown. Kras activation and Trp53 deletion in the pancreas or the lung result in pancreatic ductal adenocarinoma (PDAC) or non-small cell lung carcinoma (NSCLC), respectively, but despite the same initiating events, these tumors use branched-chain amino acids (BCAAs) differently. NSCLC tumors incorporate free BCAAs into tissue protein and use BCAAs as a nitrogen source, whereas PDAC tumors have decreased BCAA uptake. These differences are reflected in expression levels of BCAA catabolic enzymes in both mice and humans. Loss of Bcat1 and Bcat2, the enzymes responsible for BCAA use, impairs NSCLC tumor formation, but these enzymes are not required for PDAC tumor formation, arguing that tissue of origin is an important determinant of how cancers satisfy their metabolic requirements.