Biology subjects

Daniels, S. R.

Publications and source records attributed to Daniels, S. R..

3 recordsLinked to original sources

bioRxiv2024

An alternative route for β-hydroxybutyrate metabolism supports fatty acid synthesis in cancer cells

Cancer cells are exposed to diverse metabolites in the tumor microenvironment that are used to support the synthesis of nucleotides, amino acids, and lipids needed for rapid cell proliferation1-3. Recent work has shown that ketone bodies such as {beta}-hydroxybutyrate ({beta}-OHB), which are elevated in circulation under fasting conditions or low glycemic diets, can serve as an alternative fuel that is metabolized in the mitochondria to provide acetyl-CoA for the tricarboxylic acid (TCA) cycle in some tumors4-7. Here, we discover a non-canonical route for {beta}-OHB metabolism, in which {beta}-OHB can bypass the TCA cycle to generate cytosolic acetyl-CoA for de novo fatty acid synthesis in cancer cells. We show that {beta}-OHB-derived acetoacetate in the mitochondria can be shunted into the cytosol, where acetoacetyl-CoA synthetase (AACS) and thiolase convert it into acetyl-CoA for fatty acid synthesis. This alternative metabolic routing of {beta}-OHB allows it to avoid oxidation in the mitochondria and net contribute to anabolic biosynthetic processes. In cancer cells, {beta}-OHB is used for fatty acid synthesis to support cell proliferation under lipid-limited conditions in vitro and contributes to tumor growth under lipid-limited conditions induced by a calorie-restricted diet in vivo. Together, these data demonstrate that {beta}-OHB is preferentially used for fatty acid synthesis in cancer cells to support tumor growth.

cancer biology↗

bioRxiv2024

Lipid availability influences ferroptosis sensitivity in cancer cells by regulating polyunsaturated fatty acid trafficking

Ferroptosis is a form of cell death caused by lipid peroxidation that is emerging as a target for cancer therapy, highlighting the need to identify factors that govern ferroptosis susceptibility. Lipid peroxidation occurs primarily on phospholipids containing polyunsaturated fatty acids (PUFAs). Here, we show that even though extracellular lipid limitation reduces cellular PUFA levels, lipid-starved cancer cells are paradoxically more sensitive to ferroptosis. Using mass spectrometry-based lipidomics with stable isotope fatty acid labeling, we show that lipid limitation induces a fatty acid trafficking pathway in which PUFAs are liberated from triglycerides to synthesize highly unsaturated PUFAs such as arachidonic acid and adrenic acid. These PUFAs then accumulate in phospholipids, particularly ether phospholipids, to promote ferroptosis sensitivity. Therefore, PUFA levels within cancer cells do not necessarily correlate with ferroptosis susceptibility. Rather, how cancer cells respond to extracellular lipid levels by trafficking PUFAs into proper phospholipid pools dictates their sensitivity to ferroptosis.

cancer biology↗

bioRxiv2022

Convergent adaptation of true crabs (Decapoda: Brachyura) to a gradient of terrestrial environments

For much of terrestrial biodiversity, the evolutionary pathways of adaptation from marine ancestors are poorly understood, and have usually been viewed as a binary trait. True crabs, the decapod crustacean infraorder Brachyura, comprise over 7,600 species representing a striking diversity of morphology and ecology, including repeated adaptation to non-marine habitats. Here, we reconstruct the evolutionary history of Brachyura using new and published sequences of 10 genes for 344 tips spanning 88 of 109 brachyuran families. Using 36 newly vetted fossil calibrations, we infer that brachyurans most likely diverged in the Triassic, with family-level splits in the late Cretaceous and early Paleogene. By contrast, the root age is underestimated with automated sampling of 328 fossil occurrences explicitly incorporated into the tree prior, suggesting such models are a poor fit under heterogeneous fossil preservation. We apply recently defined trait-by-environment associations to classify a gradient of transitions from marine to terrestrial lifestyles. We estimate that crabs left the marine environment at least seven and up to 17 times convergently, and returned to the sea from non-marine environments at least twice. Although the most highly terrestrial- and many freshwater-adapted crabs are concentrated in Thoracotremata, Bayesian threshold models of ancestral state reconstruction fail to identify shifts to higher terrestrial grades due to the degree of underlying change required. Lineages throughout our tree inhabit intertidal and marginal marine environments, corroborating the inference that the early stages of terrestrial adaptation have a lower threshold to evolve. Our framework and extensive new fossil and natural history datasets will enable future comparisons of non-marine adaptation at the morphological and molecular level. Crabs provide an important window into the early processes of adaptation to novel environments, and different degrees of evolutionary constraint that might help predict these pathways.

evolutionary biology↗