Biology subjects

Freeman, E. C.

Publications and source records attributed to Freeman, E. C..

3 recordsLinked to original sources

bioRxiv2025

ADAR1 Regulates Lipid Remodeling through MDM2 to Dictate Ferroptosis Sensitivity

Triple-negative breast cancer (TNBC), defined by the lack of estrogen, progesterone, and HER2 receptor expressions, is aggressive and lacks targeted treatment options. Adenosine deaminase acting on RNA 1 (ADAR1) has been shown to contribute to TNBC tumorigenesis by modulating an innate immune response. However, little is known about its role in the regulation of metabolic fitness of TNBC. We tested the hypothesis that ferroptosis is an ADAR1-protected vulnerability by showing that ADAR1 knockdown sensitizes TNBC cells to ferroptosis inducers. Lipidomic analyses showed that ADAR1 loss increased the abundance of phospholipids enriched with polyunsaturated fatty acids (PUFA), of which peroxidation is the main driver of ferroptosis. Transcriptomic analyses discovered that the proto-oncogene MDM2 contributes to the lipid remodeling phenotype. A ferroptosis-focused drug screen identified FDA-approved cobimetinib as a drug-repurposing candidate to synergize with ADAR1 loss. This finding supports further basic, pre-clinical, and clinical studies to develop novel therapeutic strategies for TNBC through ADAR1-mediated metabolic regulation.

cancer biology↗

bioRxiv2023

Logging disrupts the ecology of molecules in headwater streams

Global demand for wood products is increasing forest harvest. One understudied consequence of logging is that it accelerates mobilization of dissolved organic matter (DOM) from soils to aquatic ecosystems. Here, we tested how logging changed DOM in headwaters of hardwood-dominated catchments in northern Ontario, Canada. We apply a before-after control-impact experiment across four catchments for three years. DOM concentration in streams from logged catchments quadrupled, on average, after the first year post-harvest, but resulting changes to the molecular composition of DOM persisted for at least two-years. Ultrahigh-resolution mass spectrometry revealed that DOM within logged catchments was more energy-rich and chemically diverse than in controls, with novel highly unsaturated polyphenols, carboxylic-rich alicyclic, and nitrogen-containing formulae. The molecular composition of stream DOM measured fortnightly post-harvest was most strongly associated with DOM composition within intermediate and deeper layers of contributing soils, likely due to increased hydrological connectivity post-harvest. We estimate logging increased the total annual flux of dissolved organic carbon in streams by 6.4% of extracted wood carbon, and this carbon was more likely to be released into the atmosphere. Carbon accounting of forestry, including as a natural climate solution, must now consider the transport and fate of DOM from land into water.

ecology↗

bioRxiv2022

Universal microbial reworking of dissolved organic matter along environmental gradients

Soils are losing increasing amounts of carbon annually to freshwaters as dissolved organic matter (DOM), which, if degraded, can accelerate climate change. DOM is more susceptible to degradation closer to its source and becomes increasingly dominated by the same, difficult-to-degrade compounds as degradation proceeds. However, the processes underlying DOM degradation across environments are poorly understood. Here we found DOM changed similarly along soil-aquatic gradients irrespective of differences in environmental conditions. Using ultra-high-resolution mass spectrometry, we tracked DOM along soil depths and hillslope positions in forest headwater catchments and related its composition to soil microbiomes and physical chemistry. Along depths and hillslopes, carbohydrate-like and unsaturated hydrocarbon-like compounds increased in mass, suggestive of microbial reworking of plant material. More than half of the variation in the abundance of these compounds was related to the expression of genes essential for degrading plant-derived carbohydrates. Our results implicate continuous microbial reworking in shifting DOM towards universal compounds in soils. By synthesising data from the land-to-ocean continuum, we suggest these processes can generalise across ecosystems and spatiotemporal scales. Such general degradation patterns can be leveraged to predict DOM composition and its downstream reactivity along environmental gradients to inform management of soil-to-stream carbon losses.

ecology↗