Biology subjects

Sanderson, S. M.

Publications and source records attributed to Sanderson, S. M..

4 recordsLinked to original sources

bioRxiv2024

Impaired humidity sensing reduces tick survival by preventing water homeostasis

Off-host periods are critical for ticks, representing a time when environmental stress, particularly dehydration, can impact tick survival. To prevent dehydration, ticks must be able to detect and move into high humidity areas to allow for water vapor uptake. Ionotropic receptor 93a (Ir93a), which is highly expressed in the front forelegs (location of Hallers organ), increases expression following dehydration, suggesting a role for the forelegs in humidity detection. Although the Hallers organ is suggested as the site of humidity detection in ticks, humidity detection has not been extensively examined for ticks. Here, we assessed the ability of ticks to sense humidity and how altered humidity detection impacts tick survival by manipulating the Hallers organ. Permanent (cutting or heat ablation) or temporary blocking (silicone covering) of the Hallers organ impairs the ability of the American dog tick, Dermacentor variabilis, to rest in areas necessary to maintain hydration. Impaired detection of humidity did not impact tick survival when individuals were held under stable optimal conditions. Still, variable conditions (low and high humidity gradient) reduced survival through dehydration stress and decreased energy reserves, as chronic water vapor uptake is energetically expensive. Field validation of these studies in D. variabilis confirmed that humidity detection is critical to tick survival. Lastly, modeling indicates impaired humidity detection will reduce questing tick populations, specifically in the adult stages. These studies confirm that the Hallers organ is critical for humidity sensing in ticks. Without this ability, tick survival will be impaired by potential dehydration or more rapid depletion of energy reserves.

physiology↗

bioRxiv2020

Digoxin Targets Central Carbon Metabolism and Remodels the Tumor Microenvironment

Cancer therapies targeting metabolism have been limited due to a lack of understanding of the controlling properties of vulnerable pathways. The Na+/K+ ATPase is responsible for a large portion of cellular energy demands but how these demands influence metabolism and create metabolic liabilities are not known. Using metabolomic approaches, we first show that digoxin, a cardiac glycoside widely used in humans, acts through disruption to central carbon metabolism via on target inhibition of the Na+/K+ ATPase that was fully recovered by expression of an allele resistant to digoxin. We further show in vivo that administration of digoxin inhibits glycolysis in both malignant and healthy cells, particularly within clinically relevant cardiac tissue, while exhibiting tumor-specific cytotoxic activity in an allografted soft tissue sarcoma. Single-cell expression analysis of over 31,000 cells within the sarcoma shows that acute Na+/K+ ATPase inhibition shifts the immune composition of the tumor microenvironment, leading to selective alterations to metabolic programs in specific immune cells thus acting both through tumor cell and microenvironmental (e.g. macrophage) cells. These results provide evidence that altering energy demands can be used to regulate glycolysis with cell-type specific consequences in a multicellular environment of biomedical interest.

cancer biology↗

bioRxiv2019

Dietary methionine restriction targets one carbon metabolism in humans and produces broad therapeutic responses in cancer

Nutrition exerts profound effects on health and dietary interventions are commonly used to treat diseases of metabolic etiology. Although cancer has a substantial metabolic component, the principles that define whether nutrition may be used to influence tumour outcome are unclear. Nevertheless, it is established that targeting metabolic pathways with pharmacological agents or radiation can sometimes lead to controlled therapeutic outcomes. In contrast, whether specific dietary interventions could influence the metabolic pathways that are targeted in standard cancer therapies is not known. We now show that dietary restriction of methionine (MR), an essential amino acid, and the reduction of which has aging and obesogenic properties, influences cancer outcome through controlled and reproducible changes to one carbon metabolism. This pathway metabolizes methionine and further is the target of a host of cancer interventions involving chemotherapy and radiation. MR produced therapeutic responses in chemoresistant RAS-driven colorectal cancer patient derived xenografts and autochthonous KRASG12D+/-;TP53-/- -driven soft tissue sarcomas resistant to radiation. Metabolomics revealed the therapeutic mechanisms to occur through tumor cell autonomous effects on the flux through one carbon metabolism that impacted redox and nucleotide metabolism, thus interacting with the antimetabolite or radiation intervention. Finally, in a controlled and tolerated feeding study in humans, MR resulted in similar effects on systemic metabolism as obtained in responsive mice. These findings provide evidence that a targeted dietary manipulation can affect specific tumor cell metabolism to mediate broad aspects of cancer outcome.

cancer biology↗

bioRxiv2018

Environmental factors shape methionine metabolism in p16/MTAP deleted cells

The co-deletion of a common tumor suppressor locus and neighboring metabolic gene is an attractive possible synthetic dependency of tumor suppression on metabolism. However, the general impact that these co-deletions have on metabolism, which also dependent on nutrient availability and the tissue of origin, is unknown. As a model to investigate this question, we considered a set of tissue-matched cancer cells with homozygous co-deletions in CDKN2a and MTAP, genes respectively encoding the most commonly deleted tumor suppressor p16 and an enzyme involved in methionine metabolism. A comparative metabolomics analysis revealed that while there exists a definite pan-cancer metabolic signature of MTAP-deletion, this signature was not preserved when cells were subjected to changes in the availability of methionine, serine, or cysteine, nutrients related to methionine metabolism. Notably, the heterogeneity exhibited by these cells in their responsiveness to nutrient availability dominated both MTAP status and tissue-of-origin. Furthermore, re-expression of MTAP exerted a modest effect on metabolism. Together these findings demonstrate that environmental factors, particularly nutrition and tissue identity, may overwhelm the genetic effects of collateral deletions of metabolic genes.

molecular biology↗