Biology subjects

Huang, T.-H.

Publications and source records attributed to Huang, T.-H..

10 recordsLinked to original sources

bioRxiv2025

Astrocyte cell-surface proteomics identified CD44 as an OPN/SPP1 receptor regulating lipid metabolism and glial crosstalk in Alzheimer s disease

Abstract/SummaryThe development of {beta}-amyloid (A{beta}) pathology in Alzheimers disease (AD) is accompanied by profound changes in astrocytes and microglia. How these responses are orchestrated by cell surface proteins, key mediators of cell-cell communication, remain unclear. Using in situ astrocyte cell-surface proteome profiling in 5xFAD mice, we identified a set of dysregulated surface proteins induced by A{beta} pathology, including CD44. CD44 was selectively upregulated in plaque-adjacent astrocytes and interacted with osteopontin (OPN), encoded by the disease-associated microglia gene Spp1, to promote lipid accumulation, and this effect is {gamma}-secretase dependent. Astrocytic CD44 in turn regulated Spp1 expression and microglial activity. Conditional deletion of Cd44 in adult astrocytes of 5xFAD mice attenuated glial reactivity, reduced A{beta} pathology, and improved cognition. These findings define a plaque-proximal OPN-CD44 axis that controls astrocyte lipid metabolism and glial activity, positioning CD44 as a surface-accessible therapeutic target in AD.

neuroscience↗

bioRxiv2024

Restraint of melanoma progression by cells in the local skin environment

Keratinocytes, the dominant cell type in the melanoma microenvironment during tumor initiation, exhibit diverse effects on melanoma progression. Using a zebrafish model of melanoma and human cell co-cultures, we observed that keratinocytes undergo an EMT-like transformation in the presence of melanoma, reminiscent of their behavior during wound healing. Surprisingly, overexpression of the EMT transcription factor Twist in keratinocytes led to improved overall survival in zebrafish melanoma models, despite no change in tumor initiation rates. This survival benefit was attributed to reduced melanoma invasion, as confirmed by human cell co-culture assays. Single-cell RNA-sequencing revealed a unique melanoma cell cluster in the Twist-overexpressing condition, exhibiting a more differentiated, less invasive phenotype. Further analysis nominated homotypic jam3b-jam3b and pgrn-sort1a interactions between Twist-overexpressing keratinocytes and melanoma cells as potential mediators of the invasive restraint. Our findings suggest that EMT in the tumor microenvironment may paradoxically limit melanoma invasion through altered cell-cell interactions.

cancer biology↗

bioRxiv2023

S100A8/A9 predicts triple-negative breast cancer response to PIM kinase and PD-1/PD-L1 inhibition

It remains elusive why some triple-negative breast cancer (TNBC) patients respond poorly to existing therapies while others respond well. Our retrospective analysis of historical gene expression datasets reveals that increased expression of immunosuppressive cytokine S100A8/A9 in early-stage tumors is robustly associated with subsequent disease progression in TNBC. Although it has recently gained recognition as a potential anticancer target, S100A8/A9 has not been integrated into clinical study designs evaluating molecularly targeted therapies. Our small molecule screen has identified PIM kinase inhibitors as capable of decreasing S100A8/A9 expression in multiple cell types, including TNBC and immunosuppressive myeloid cells. Furthermore, combining PIM inhibition and immune checkpoint blockade induces significant antitumor responses, especially in otherwise resistant S100A8/A9-high PD-1/PD-L1-positive tumors. Importantly, serum S100A8/A9 levels mirror those of tumor S100A8/A9 in a syngeneic mouse model of TNBC. Thus, our data suggest that S100A8/A9 could be a predictive and pharmacodynamic biomarker in clinical trials evaluating combination therapy targeting PIM and immune checkpoints in TNBC and encourage the development of S100A8/A9-based liquid biopsy tests.

cancer biology↗

bioRxiv2022

The Impact of Population Stratification on the Analysis of Multimodal Neuroimaging Derived Measures

Magnetic resonance imaging (MRI) studies of the human brain are now attaining larger sample sizes with more diverse samples. However, population stratification, a key factor driving heterogeneity and confounding of associations, is seldom accounted for in neuroimaging analyses. To investigate this issue, we assessed the impact of population stratification on multimodal imaging measures using baseline data from the Adolescent Brain Cognitive Development (ABCD) StudySM (n = 10,748). Given this sociodemographically diverse sample, which broadly reflects the population composition of the United States, we performed a thorough evaluation of the impact of population stratification on derived neuroimaging metrics across five different imaging modalities: task functional MRI (task fMRI), resting state functional MRI (rsMRI), diffusion tensor images (DTI), restricted spectrum images (RSI), and structural T1 MRI (sMRI). We used parental income level as an example to highlight the impact of population stratification in confounding brain-wide associations. We show that derived metrics from structural images have up to three times more signal related to population stratification than do functional images. Controlling for population stratification in statistical models leads to a substantial reduction in the association strength between variables of interests and imaging measures, indicating the scale of potential bias. Moreover, because of unequal access to resources (such as income) across ancestral groups in United States, population stratification effects on imaging features may bias associations between parental income levels and imaging features, as we demonstrate. Our results provide a guide for researchers to critically examine the impact of population stratification and to assist in avoiding spurious brain-behavior associations. HighlightsO_LIHere, we conduct a comprehensive survey of the confounding impact of population stratification in large-scale imaging studies. C_LIO_LIMorphological features from structural imaging appear to be more susceptible to the confounding effects of population stratification than do functional imaging features. C_LIO_LIThe population stratification tends to inflates the association strengths between the variable of interest and imaging features. C_LIO_LIWhen the variable of interest is highly colinear with the population stratification, such as income levels, brain associations cannot be differentiated and may be misattributed as mediating effects. C_LIO_LIIt is critical to account for population stratification in imaging analyses. C_LI

neuroscience↗

bioRxiv2022

Epigenetic reprogramming of melanoma cell state through fatty acid β-oxidation and Toll like receptor 4 signaling

Tumor cells respond to a host of factors from the local microenvironment. Microenvironmental fatty acids can be used by melanoma cells for fuel, but their effects on transcription and epigenetics are still unclear. Here, we show that the fatty acid {beta}-oxidation (FAO) pathway integrates signaling and epigenetics to drive melanoma progression. Using transgenic zebrafish and human cell lines, we find that octanoate, a medium-chain fatty acid, increases tumorigenesis. Octanoate is metabolized via the FAO/ACLY axis into acetyl-CoA, leading to increased histone acetylation. Transcriptomic and epigenetic analyses demonstrate a convergence of inflammatory gene signatures in octanoate-treated melanoma cells. This signature is mediated by TLR4/MyD88 signaling, which is activated by saturated fatty acids like octanoate. Genetic inactivation of either FAO enzymes or TLR4/MyD88 inhibits alterations in histone acetylation, and rescues octanoate-tumor promoting effects. Together, these data demonstrate clear evidence linking fatty acid metabolism and epigenetics to melanoma pathogenesis through TLR4 signaling.

cancer biology↗

bioRxiv2022

Lipid droplets are a metabolic vulnerability in melanoma

Melanoma exhibits numerous transcriptional cell states including neural crest-like cells as well as pigmented melanocytic cells. How these different cell states relate to distinct tumorigenic phenotypes remains unclear. Here, we use a zebrafish melanoma model to identify a transcriptional program linking the pigmented cell state to a dependence on lipid droplets, the specialized organelle responsible for lipid storage. Single-cell RNA-sequencing of these tumors show a concordance between genes regulating pigmentation and those involved in lipid and oxidative metabolism. This state is conserved in human melanoma specimens. This state demonstrates increased fatty acid uptake, an increased number of lipid droplets, and dependence upon oxidative metabolism. Genetic and pharmacologic suppression of lipid droplet production is sufficient to disrupt oxidative metabolism and slow melanoma growth in vivo. Because the pigmented cell state is linked to poor outcomes in patients, these data indicate a metabolic vulnerability in melanoma that depends on the lipid droplet organelle.

cancer biology↗

bioRxiv2020

Anatomic position determines oncogenic specificity in melanoma

Oncogenic alterations to DNA are not transforming in all cellular contexts1,2. This may be due to pre-existing transcriptional programs in the cell of origin. Here, we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype arises on the palms of the hands, soles of the feet, or under the nails3. We sequenced the DNA of cutaneous and acral melanomas from a large cohort of human patients and found a specific enrichment for BRAF mutations in cutaneous melanoma but CRKL amplifications in acral melanoma. We modeled these changes in transgenic zebrafish models and found that CRKL-driven tumors predominantly formed in the fins of the fish. The fins are the evolutionary precursors to tetrapod limbs, indicating that melanocytes in these acral locations may be uniquely susceptible to CRKL. RNA profiling of these fin/limb melanocytes, compared to body melanocytes, revealed a positional identity gene program typified by posterior HOX13 genes. This positional gene program synergized with CRKL to drive tumors at acral sites. Abrogation of this CRKL-driven program eliminated the anatomic specificity of acral melanoma. These data suggest that the anatomic position of the cell of origin endows it with a unique transcriptional state that makes it susceptible to only certain oncogenic insults.

cancer biology↗

bioRxiv2020

Cell state diversity promotes metastasis through heterotypic cluster formation in melanoma

In melanoma, transcriptional profiling has revealed multiple co-existing cell states, including proliferative versus invasive sub-populations that have been posited to represent a "go or grow" tradeoff. Both of these populations are maintained in tumors, but how they physically interact to promote metastasis is unknown. We demonstrate that these subpopulations form spatially structured heterotypic clusters that cooperate in the seeding of metastasis. We unexpectedly found that INV cells were tightly adherent to each other, and formed clusters with a rim of PRO cells. Intravital imaging demonstrated cooperation between these populations, in which the INV cells facilitated the spread of less metastatic PRO cells. We identified the TFAP2 neural crest transcription factor as a master regulator of both clustering and the PRO/INV states. Our data suggest a framework for the co-existence of these two divergent cell populations, in which differing cell states form heterotypic clusters that promote metastasis via cell-cell cooperation.

cancer biology↗

bioRxiv2020

ZmMTOPVIB is essential for double-strand break formation and bipolar spindle assembly in maize meiosis

The programmed formation of DNA double-strand breaks (DSBs) during early meiosis is catalyzed by SPO11, a conserved ortholog to the A subunit of an archaeal topoisomerase VI (TopoVI) which functions as a hetero-tetramer comprising two A and two B subunits. An essential role of the meiotic TopoVI B subunit (TopVIB) in DSB formation has been reported in mouse, Arabidopsis and rice. Very recently, rice MTopVIB was revealed to have an unexpected role in meiotic bipolar spindle assembly, highlighting multiple functions of MTopVIB during rice meiosis. In this work, the meiotic TopVIB in maize (ZmMTOPVIB) was characterized. The ZmmtopVIB mutant plants exhibited normal vegetative growth but male and female sterility. DSB formation is abolished in mutant meiocytes. Despite normal assembly of axial elements, synapsis was severely affected and homologous pairing was disrupted in mutants. Importantly, we showed that bipolar spindle assembly was also affected in ZmmtopVIB, resulting in triad and polyad formation. Overall, our results demonstrate that ZmMTOPVIB plays critical roles in DSB formation and homologous recombination. In addition, the newly-discovered function of MTOPVIB in bipolar spindle assembly is likely conserved across different monocots. One-sentence summaryThe dual roles of MTOPVIB in regulating meiotic DSB formation and bipolar spindle assembly are evolutionarily conserved in monocot plants.

cell biology↗

bioRxiv2018

Repression of Dlx1/2 Signaling by Nolz-1/Znf503 is Essential for Parcellation of the Striatal Complex into Dorsal and Ventral Striatum

The division of the striatum into dorsal and ventral districts is of central clinical importance. The dorsal striatum is differentially affected in Huntingtons disease, dopamine in the ventral striatum is differentially spared in Parkinsons disease, and human brain imaging studies implicate the ventral striatum in addictive disorders. If fits that the dorsal striatum contains the cells of origin of the direct and indirect basal ganglia pathways for motor control. The ventral striatum is a node in neural circuits related to motivation and affect. Despite these striking neurobiologic contrasts, there is almost no information about how the dorsal and ventral divisions of the striatum are set up during development. Here, we demonstrate that interactions between the two key transcription factors Nolz-1 and Dlx1/2 control the migratory paths of developing striatal neurons to the dorsal or ventral striatum. Moreover, these same transcription factors control the cell identity of striatal projection neurons in both the dorsal and ventral striatum including the cell origin of the direct and indirect pathways. We show that Nolz-1 suppresses Dlx1/2 expression. Deletion of Nolz-1 or over-expression of Dlx1/2 can produce a striatal phenotype characterized by withered dorsal striatum and a swollen ventral striatum, and that we can rescue this phenotype by manipulating the interactions between Nolz-1 and Dlx1/2 transcription factors. This evidence suggests that the fundamental basis for divisions of the striatum known to be differentially vulnerable at maturity is already encoded by the time embryonic striatal neurons begin their migrations into the developing striatum.

neuroscience↗