Biology subjects

Kang, T.-Y.

Publications and source records attributed to Kang, T.-Y..

5 recordsLinked to original sources

bioRxiv2025

Interplay between cytokine and FGF2 signaling in induction of entosis and vasculogenic mimicry response in glioblastoma

Tumor vascularization is critical to survival of cancer cells, but is frequently perturbed leading to disorganized angiogenesis and emergence of alternative means of delivery of oxygen and nutrients, such as vasculogenic mimicry (VM). Understanding of VM and its relationship to endothelial vascularization has been hampered by the lack of comprehensive combination of in vivo clinical data and relevant in vitro models. We address this challenge by analyzing glioblastoma (GBM) tumors and clinically isolated cancer cells. This analysis strongly suggests a key role of macrophage-induced controlled cell death in emergence of VM. The results further point to entosis of cancer cells as a critical intermediate state in this process, enabled by mechano-chemical cell heterogeneity. We find evidence that macrophages can regulate endothelial angiogenesis and VM as two alternative vascularization mechanisms. These results reveal mechanistic underpinnings of VM and pave the way to predictive analysis of tumor progression.

cancer biology↗

bioRxiv2024

Specification of human regional brain lineages using orthogonal gradients of WNT and SHH in organoids

The repertory of neurons generated by progenitor cells depends on their location along antero-posterior and dorso-ventral axes of the neural tube. To understand if recreating those axes was sufficient to specify human brain neuronal diversity, we designed a mesofluidic device termed Duo-MAPS to expose induced pluripotent stem cells (iPSC) to concomitant orthogonal gradients of a posteriorizing and a ventralizing morphogen, activating WNT and SHH signaling, respectively. Comparison of single cell transcriptomes with fetal human brain revealed that Duo-MAPS-patterned organoids generated the major neuronal lineages of the forebrain, midbrain, and hindbrain. Morphogens crosstalk translated into early patterns of gene expression programs predicting the generation of specific brain lineages. Human iPSC lines from six different genetic backgrounds showed substantial differences in response to morphogens, suggesting that interindividual genomic and epigenomic variations could impact brain lineages formation. Morphogen gradients promise to be a key approach to model the brain in its entirety.

neuroscience↗

bioRxiv2023

Dynamic decoding of VEGF signaling and coordinated control of multiple phenotypes by the Src-TEM4-YAP pathway

Responses of endothelial cells to elevated levels of Vascular Endothelial Growth Factor (VEGF), frequently accompanying local decrease in oxygen supply, include loosening of cell contacts, rearrangement of cells in the process of vessel remodeling and ultimately, angiogenic growth. How these complex processes, occurring on diverse time scales, are coordinated and how they are guided by a single key signaling input, is still incompletely understood. Here we show that the various phenotypic responses associated with VEGF signaling are controlled at different steps of a pathway involving sequential activation of Src, TEM4, YAP and components of pro-angiogenic Notch signaling. Strikingly, due to feedback regulation at different pathway levels, the functional outcomes are controlled by oscillations of the pathway components occurring on distinct time scales. Deeper pathway layers integrate faster upstream responses and control progressively slower phenotypic outcomes. This signal decoding pathway organization can ensure a high degree of complexity in a vital physiological process.

systems biology↗

bioRxiv2022

Spatial-temporal order-disorder transition in angiogenic NOTCH signaling controls cell fate specification

Angiogenesis is a morphogenic process resulting in the formation of new blood vessels from pre-existing ones, usually in hypoxic micro-environments. The initial steps of angiogenesis depend on robust differentiation of oligopotent endothelial cells into the Tip and Stalk phenotypic cell fates, controlled by NOTCH-dependent cell-cell communication. The dynamics of spatial patterning of this cell fate specification are only partially understood. Here, by combining a controlled experimental angiogenesis model with mathematical and computational analyses, we find that the regular spatial Tip-Stalk cell patterning can undergo an order-disorder transition at a relatively high input level of a pro-angiogenic factor VEGF. The resulting differentiation is robust but temporally unstable for most cells, with only a subset of presumptive Tip cells leading sprout extensions. We further find that sprouts form in a manner maximizing their mutual distance, consistent with a Turing-like model that may depend on local enrichment and depletion of fibronectin. Together, our data suggest that NOTCH signaling mediates a robust way of cell differentiation enabling but not instructing subsequent steps in angiogenic morphogenesis, which may require additional cues and self-organization mechanisms. This analysis can assist in further understanding of cell plasticity underlying angiogenesis and other complex morphogenic processes. Significance StatementWe investigate the spatial and temporal patterns of Tip/Stalk specification and the ensuing angiogenic sprouting by using a novel controlled micro-engineered experimental model of angiogenesis and a set of mathematical models of the spatially resolved, cell population-level VEGF-NOTCH signaling. Our analysis provides a dynamic view of the initial step of angiogenesis, revealing fluctuations in its onset, and features suggesting transitions between order and disorder in cell organization. These findings suggest how a potentially very restrictive patterning mechanism can become sensitive to a variety of environmental cues. This sensitivity can be crucial for proper vascularization of a damaged organ, and may suggest new ways of analyzing angiogenesis in the context of cancer and other pathologies. This analysis also suggests a framework for understanding of other instances of NOTCH-mediated patterning processes.

systems biology↗

bioRxiv2019

Pericytes enable effective angiogenesis in the presence of pro inflammatory signals

Angiogenesis frequently occurs in the context of acute or persistent inflammation. The complex interplay of pro-inflammatory and pro-angiogenic cues is only partially understood. Using a new experimental model permitting exposure of developing blood vessel sprouts to multiple combinations of diverse biochemical stimuli and juxtacrine cell interactions, we present evidence that a pro-inflammatory cytokine, tumor necrosis factor (TNF), can have both pro- and anti-angiogenic effects, depending on the dose and the presence of pericytes. In particular, we find that pericytes can rescue and enhance angiogenesis in the presence of otherwise inhibitory high TNF doses. This sharp switch from pro- to anti-angiogenic effect of TNF observed with an escalating dose of this cytokine, as well as the effect of pericytes are explained by a mathematical model trained on the biochemical data. Furthermore, this model was predictive of the effects of diverse combinations of pro-and anti-inflammatory cues, and variable pericyte coverage. The mechanism supports the effect of TNF and pericytes as modulating signaling networks impinging in Notch signaling and specification of the Tip and Stalk phenotypes. This integrative analysis elucidates the plasticity of the angiogenic morphogenesis in the presence of diverse and potentially conflicting cues, with immediate implications for many physiological and pathological settings.

developmental biology↗