Biology subjects

Stine, C.

Publications and source records attributed to Stine, C..

5 recordsLinked to original sources

bioRxiv2025

S1PR3 mediates glial stimulated tumor invasion in response to interstitial fluid flow

Cellular invasion is a primary challenge to complete resection and treatment of glioblastoma, the most aggressive and deadly primary brain tumor. The brain tumor microenvironment actively stimulates glioma invasion through a multitude of cellular, chemical, and biophysical cues. We and others have shown elevated interstitial fluid flow at the tumor border is one such biophysical cue that directly stimulates invasion through tumor-intrinsic signaling and, in other tumor types, priming of cancer-associated stromal cells. It is currently unclear if interstitial flow similarly primes neuroglial cells to promote glioma cell dissemination and can be targeted for therapeutic purposes. Here, we show elevated interstitial flow upregulates expression of sphingosine-1-phosphate receptor 3 (S1PR3) in glial astrocytes and microglia, which drives glioma cell invasion via chemotaxis. Flow-induced expression of glial S1PR3 is tumor-independent and displays a biphasic relationship to fluid shear stress magnitude in vitro and flow rate in vivo. Inhibition of glial S1PR3 in a tissue engineered culture model and orthotopic mouse model abrogates flow-stimulated invasion, demonstrating a tumor-extrinsic approach to limiting glioblastoma progression. Given prior evidence of a pro-inflammatory role for glial S1PR3, identification of S1PR3 as a disease-agnostic marker of flow-stimulated glia may also have therapeutic implications across myriad neuropathologies.

cancer biology↗

bioRxiv2025

Identification of a stress-sensitive endogenous opioid-containing neuronal population in the paranigral ventral tegmental area.

Nociceptin/orphanin FQ (N/OFQ), an endogenous opioid neuropeptide, and its G-protein coupled receptor NOPR have been implicated in motivation, feeding behaviors, and aversion. Stress-induced dysfunction in these states is central to the development of numerous psychiatric disorders, and the N/OFQ-NOPR systems role in reward- and stress-related responses has driven broad interest in NOPR as a therapeutic target for anxiety and depression. However, the impact of stress on N/OFQ signaling in the context of its influence on discrete midbrain reward circuitry remains unknown. To this end, we focused on a possible candidate population of N/OFQ neurons in the paranigral ventral tegmental area (pnVTAPNOC) that have been shown to act locally on NOPR-containing VTA dopamine neurons to suppress motivation. Here we report and characterize pnVTAPNOC sensitivity to stress exposure and identify a functional excitatory and inhibitory afferent input to this subpopulation from the lateral hypothalamus (LH). Our results indicate that pnVTAPNOC neurons become recruited during exposure to a range of acute stressor types, whereas the GABAergic input from the LH to this population is suppressed by predator odor stress, providing a mechanism for disinhibition of these neurons. These findings suggest that this N/OFQ population in the pnVTA could act as a critical bridge between stress and motivation through interactions with upstream hypothalamic circuitry.

neuroscience↗

bioRxiv2024

Developmental and adult striatal patterning of nociceptin ligand marks striosomal population with direct dopamine projections

Circuit influences on the midbrain dopamine system are crucial to adaptive behavior and cognition. Recent developments in the study of neuropeptide systems have enabled high-resolution investigations of the intersection of neuromodulatory signals with basal ganglia circuitry, identifying the nociceptin/orphanin FQ (N/OFQ) endogenous opioid peptide system as a prospective regulator of striatal dopamine signaling. Using a prepronociceptin-Cre reporter mouse line, we characterized highly selective striosomal patterning of Pnoc mRNA expression in mouse dorsal striatum, reflecting early developmental expression of Pnoc. In the ventral striatum, Pnoc expression was was clustered across the nucleus accumbens core and medial shell, including in adult striatum. We found that PnoctdTomato reporter cells largely comprise a population of dopamine receptor D1 (Drd1) expressing medium spiny projection neurons localized in dorsal striosomes, known to be unique among striatal projections neurons for their direct innervation of midbrain dopamine neurons. These findings provide new understanding of the intersection of the N/OFQ system among basal ganglia circuits with particular implications for developmental regulation or wiring of striatal-nigral circuits.

neuroscience↗

bioRxiv2023

Non-invasive measurement of intra-tumoral fluid dynamics with localized convolutional function regression

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a routine method to non-invasively quantify perfusion dynamics in tissues. The standard practice for analyzing DCE-MRI data is to fit an ordinary differential equation to each voxel. Recent advances in data science provide an opportunity to move beyond existing methods to obtain more accurate measurements of fluid properties. Here, we developed a localized convolutional function regression that enables simultaneous measurement of interstitial fluid velocity, diffusion, and perfusion in 3D. We validated the method computationally and experimentally, demonstrating accurate measurement of fluid dynamics in situ and in vivo. Applying the method to human MRIs, we observed tissue-specific differences in fluid dynamics, with an increased fluid velocity in breast cancer as compared to brain cancer. Overall, our method represents an improved strategy for studying interstitial flows and interstitial transport in tumors and patients. We expect that it will contribute to the better understanding of cancer progression and therapeutic response. One-Sentence SummaryA physics-informed computational method enables accurate and efficient measurement of fluid dynamics in individual patient tumors and demonstrates differences between tissues.

bioengineering↗

bioRxiv2023

Development of a genetically-encoded sensor for probing endogenous nociceptin opioid peptide release

Nociceptin/orphanin-FQ (N/OFQ) is a recently appreciated critical opioid peptide with key regulatory functions in several central behavioral processes including motivation, stress, feeding, and sleep. The functional relevance of N/OFQ action in the mammalian brain remains unclear due to a lack of high-resolution approaches to detect this neuropeptide with appropriate spatial and temporal resolution. Here we develop and characterize NOPLight, a genetically encoded sensor that sensitively reports changes in endogenous N/OFQ release. We characterized the affinity, pharmacological profile, spectral properties, kinetics, ligand selectivity, and potential interaction with intracellular signal transducers of NOPLight in vitro. Its functionality was established in acute brain slices by exogeneous N/OFQ application and chemogenetic induction of endogenous N/OFQ release from PNOC neurons. In vivo studies with fibre photometry enabled direct recording of NOPLight binding to exogenous N/OFQ receptor ligands, as well as detection of endogenous N/OFQ release within the paranigral ventral tegmental area (pnVTA) during natural behaviors and chemogenetic activation of PNOC neurons. In summary, we show here that NOPLight can be used to detect N/OFQ opioid peptide signal dynamics in tissue and freely behaving animals.

neuroscience↗