Biology subjects

Cunningham, K.

Publications and source records attributed to Cunningham, K..

3 recordsLinked to original sources

bioRxiv2023

The helminth TGF-beta mimic TGM4 is a modular ligand that binds CD44, CD49d and TGF-beta receptors to preferentially target myeloid cells

The murine helminth parasite Heligmosomoides polygyrus expresses a family of modular proteins which, replicating the functional activity of the immunomodulatory cytokine TGF-{beta}, have been named TGM (TGF-{beta} Mimic). Multiple domains bind to different receptors, including TGF-{beta} receptors T{beta}RI (ALK5) and T{beta}RII through domains 1-3, and prototypic family member TGM1 binds the cell surface co-receptor CD44 through domains 4-5. This allows TGM1 to induce T lymphocyte Foxp3 expression, characteristic of regulatory (Treg) cells, and to activate a range of TGF-{beta}-responsive cell types. In contrast, a related protein, TGM4, targets a much more restricted cell repertoire, primarily acting on myeloid cells, with less potent effects on T cells and lacking activity on other TGF-{beta}-responsive cell types. TGM4 binds avidly to myeloid cells by flow cytometry, and can outcompete TGM1 for cell binding. Analysis of receptor binding in comparison to TGM1 reveals a 10-fold higher affinity than TGM1 for TGF{beta}R-I (T{beta}RI), but a 100-fold lower affinity for T{beta}RII through Domain 3. Consequently, TGM4 is more dependent on co-receptor binding; in addition to CD44, TGM4 also engages CD49d (Itga4) through Domains 1-3, as well as CD206 and Neuropilin-1 through Domains 4 and 5. TGM4 was found to effectively modulate macrophage populations, inhibiting lipopolysaccharide-driven inflammatory cytokine production and boosting interleukin (IL)-4-stimulated responses such as Arginase-1 in vitro and in vivo. These results reveal that the modular nature of TGMs has allowed the fine tuning of the binding affinities of the T{beta}R- and co-receptor binding domains to establish cell specificity for TGF-{beta} signalling in a manner that cannot be attained by the mammalian cytokine.

immunology↗

bioRxiv2023

Extracellular matrix sulfation in the tumor microenvironment stimulates cancer stemness and invasiveness

Tumor extracellular matrices (ECM) exhibit aberrant changes in composition and mechanics compared to normal tissues. Proteoglycans (PG) are vital regulators of cellular signaling in the ECM with ability to modulate receptor tyrosine kinase (RTK) activation via their sulfated glycosaminoglycan (sGAG) side chains. However, their role on tumor cell behavior is controversial. Here, we demonstrate that PGs are heavily expressed in lung adenocarcinoma patients in correlation with invasive phenotype and poor prognosis. We developed a bioengineered human lung tumor model which recapitulates the increase of sGAGs in tumors in an organotypic matrix with independent control of stiffness, viscoelasticity, ligand density and porosity. Our model reveals that increased sulfation stimulates extensive proliferation, epithelial-mesenchymal transition and stemness in cancer cells. We identified the FAK-PI3K-mTOR signaling axis as a mediator of sulfation-induced molecular changes in cells upon activation of a distinct set of RTKs within tumor-mimetic hydrogels. We demonstrate that the transcriptomic landscape of tumor cells in response to increased sulfation resembles native PG-rich patient tumors through employing integrative omics and network modeling approaches.

bioengineering↗

bioRxiv2022

Adaptive structural and functional evolution of the placenta protects fetal growth in high elevation deer mice

Environmental hypoxia challenges female reproductive physiology in placental mammals, increasing rates of gestational complications. Adaptation to high elevation has limited many of these effects in humans and other mammals, offering potential insight into the developmental processes that lead to and protect against hypoxia-related gestational complications. However, our understanding of these adaptations has been hampered by a lack of experimental work linking the functional, regulatory, and genetic underpinnings of gestational development in locally-adapted populations. Here, we dissect high-elevation adaptation in the reproductive physiology of deer mice, (Peromyscus maniculatus), a rodent species with an exceptionally broad elevational distribution that has emerged as a model for hypoxia adaptation. Using experimental acclimations, we show that lowland mice experience pronounced fetal growth restriction when challenged with gestational hypoxia, while highland mice maintain normal growth by expanding the compartment of the placenta that facilitates nutrient and gas exchange between dam and fetus. We then use compartmentspecific transcriptome analyses to show that adaptive structural remodeling of the placenta is coincident with widespread changes in gene expression within this same compartment. Genes associated with fetal growth in deer mice significantly overlap with genes involved in human placental development, pointing to conserved or convergent pathways underlying these processes. Finally, we overlay our results with genetic data from natural populations to identify can-didate genes and genomic features that contribute to these placental adaptations. Collectively, these experiments advance our understanding of adaptation to hypoxic environments by revealing physiological and genetic mechanisms that shape fetal growth trajectories under maternal hypoxia. Significance StatementResidence at high elevations is associated with higher risk pregnancies and low birth weight, yet the causal mechanisms remain poorly understood. Using a high elevation-adapted rodent model, we investigated the physiological traits that explain fetal growth trajectories in low oxygen environments, and how evolutionary adaptation has modified these traits. We showed that high- and low-elevation populations of deer mice differ in their susceptibility to fetal growth restriction during gestational hypoxia and that these population-level differences are associated with structural and transcriptomic changes in the placenta. We further link placental gene expression to genomic features under selection at high elevation. Our findings identify adaptations that are likely relevant to offsetting the effects of hypoxia on fetal and placental development across mammals.

evolutionary biology↗