Eaton, E. | Search bioRxiv

bioRxiv2024

Ether lipids influence cancer cell fate by modulating iron uptake

Cancer cell fate has been widely ascribed to mutational changes within proteincoding genes associated with tumor suppressors and oncogenes. In contrast, the mechanisms through which the biophysical properties of membrane lipids influence cancer cell survival, dedifferentiation and metastasis have received little scrutiny. Here, we report that cancer cells endowed with high metastatic ability and cancer stem celllike traits employ ether lipids to maintain low membrane tension and high membrane fluidity. Using genetic approaches and lipid reconstitution assays, we show that these ether lipid-regulated biophysical properties permit non-clathrin-mediated iron endocytosis via CD44, resulting in significant increases in intracellular redox-active iron and enhanced ferroptosis susceptibility. Using a combination of in vitro threedimensional microvascular network systems and in vivo animal models, we show that loss of ether lipids from plasma membranes also strongly attenuates extravasation, metastatic burden and cancer stemness. These findings illuminate a mechanism whereby ether lipids in carcinoma cells serve as key regulators of malignant progression while conferring a unique vulnerability that can be exploited for therapeutic intervention.

cancer biology↗

bioRxiv2023

Population genomics of Aspergillus sojae is shaped by the food environment

Traditional fermented foods often contain specialized microorganisms adapted to the unique food environment. For example, the filamentous mold Aspergillus oryzae, used in sake fermentation, has evolved to thrive in starch-rich conditions compared to its wild ancestor, Aspergillus flavus. Similarly, Aspergillus sojae is used in soybean-based food fermentations (e.g. miso and shochu) and is closely related to Aspergillus parasiticus. Here, we investigated the impact of long-term A. sojae usage in soybean fermentation on population structure, genome variation, and phenotypic traits. We analyzed 12 A. sojae and 10 A. parasiticus genomes, along with phenotypic characteristics of 15 isolates. Our results revealed that A. sojae isolates formed a distinct population separate from A. parasiticus and displayed remarkably low levels of genetic diversity, indicative of a recent clonal expansion. Genome comparisons revealed numerous loss-of-function mutations in A. sojae, notably in genes responsible for secondary metabolite production, including genes in the aflatoxin encoding gene cluster. Consequently, A. sojae lacked aflatoxin production, while it varied among A. parasiticus isolates. No other significant differences were observed in growth rates or other measured phenotypic traits between A. sojae and A. parasiticus. These findings suggest that A. sojae may have evolved from a population of A. parasiticus and lost the ability to produce some secondary metabolites. To elucidate the phenotypic differences between A. sojae and A. parasiticus, future work should focus on the influence of wild and food-associated strains on the sensory aspects and microbial community dynamics of fermented soy products. Significance StatementLike plants and animals, microbes were also domesticated by humans, however relatively little is known about how the process of domestication shapes microbial genomes and traits. We found that isolates of Aspergillus sojae, a mold used in the production of miso and soy sauce, makeup a less toxic group that is genetically distinct from its closely related wild ancestor Aspergillus parasiticus. Our analyses shed new light on commonalities observed across filamentous molds adapted to the food environment.

evolutionary biology↗