Proliferating cells need a standard electron-accepting molecule known as NAD+ for the oxygen-driven production of large biomolecules, which are essential building blocks of cells. A June publication in Nature Metabolism co-led by Ludwig MIT’s Matthew Vander Heiden quantitatively demonstrated that when NAD+ is in short supply—as it is in low-oxygen conditions that are common in tumors—reactions that generate the precursors of lipids shut down, creating a supply bottleneck that snuffs out lipid biosynthesis. The shortage of oxygen does not seem to tax energy supplies in the cancer cells tested, however, as giving them more energy-generating molecules did not affect their proliferation. As much as 30% of the oxygen used by cancer cells, it turns out, can go to lipid biosynthesis. Matthew and his colleagues found that the access to a metabolic byproduct known as acetate can relieve dependency on NAD+ for lipid synthesis because it allows cells to bypass the NAD+-dependent steps of lipid production. They also showed that across tumor types, the elevated expression of genes involved in responses to oxygen starvation is accompanied by low expression of genes essential to lipid production. The study provides a mechanistic explanation for why cancer cells depend on imported lipids for growth during oxygen starvation and suggests that drugs that interfere with lipid import may be useful for cancer therapy.
Read the study: Cancer cells depend on environmental lipids for proliferation when electron acceptors are limited, Nature Metabolism, 2022 June 23
This article appeared in the September 2022 issue of Ludwig Link. Click here to download a PDF (1 MB).