Biology subjects

Henry, C. J.

Publications and source records attributed to Henry, C. J..

6 recordsLinked to original sources

bioRxiv2026

Early Epigenetic and Metabolic Responses to the Adipocyte Secretome Reveal Stress-Adaptive States in Triple-Negative Breast Cancer

Obesity is a well-established risk factor for triple-negative breast cancer (TNBC), yet how adipocyte-derived signals reprogram cancer cell metabolism and chromatin states remains poorly defined. Here, we investigate how adipocyte-driven lipogenesis reshapes metabolic-epigenetic coupling to support stress-adaptive cell states and functional changes in epithelial TNBC cells. Using an integrated multi-omic approach, we combine RNA sequencing (RNA-seq), chromatin accessibility (ATAC-seq), metabolic flux modeling, and functional metabolic assays in lipogenic BT-549 cells. Computational modeling trained on RNA-seq predicts shifts in metabolic pathway usage, including enhanced NAD-linked metabolism. RNA-seq reveals a predominance of gene activation, consistent with ATAC-seq data showing a strong bias toward increased accessibility. Regions of increased accessibility are enriched for stress-adaptive and antioxidant pathways, including superoxide dismutase 2 (SOD2) and metallothioneins (MT1F, MT1E, MT2A). Functionally, lipogenic cells exhibit increased spare respiratory capacity, altered ATP-linked respiration, elevated extracellular acidification, and reduced reactive oxygen species (ROS) accumulation, consistent with a bioenergetically flexible, stress-adaptive metabolic state. Together, these findings reveal that adipocyte-driven metabolic rewiring promotes selective chromatin opening and activation of stress-adaptive gene programs, enabling TNBC cells to buffer oxidative pressure for enhanced proliferation and survival after exposure to the adipocyte secretome.

cancer biology↗

bioRxiv2024

Genomic Reconstruction and Dietary Response Assessment of Three Acutalibacteraceae Bacteria Isolated from Fecal Samples of Singapore Subjects.

1.Clostridium leptum, a key player in gut butyrate production, has a profound impact on various facets of intestinal health. A recent clinical trial highlighted a significant increase in the relative abundance of this species in response to dietary interventions using beneficial oils. We isolated microbial strains corresponding to "Clostridium leptum" (at the 16S rRNA gene similarity level) and sequenced their genomes. All three genomes were successfully reconstructed, maintaining the chromosome as a single contig. Subsequent genome-wide analysis unveiled the phylogenetic diversity of the isolates, including the discovery of a new species - Gallacutalibacter singaporense. Based on the reconstructed metabolic model, we predicted the growth condition patterns of this new species and confirmed the predictions in vitro. Leveraging the assembled genomes, we dissected the components of the strong dietary intervention response signal previously ascribed to "C. leptum" and revealed distinct individual dynamics of all three bacteria in the clinical trial context. The transitional behavior of the novel species, in particular, revealed intriguing patterns, blazing the path to uncovering previously unrecognized interactions along the diet - gut microbiome - human health axis.

microbiology↗

bioRxiv2024

The T-cell niche tunes immune function through modulation of the cytoskeleton and TCR-antigen forces

Obesity is a major public health crisis given its rampant growth and association with an increased risk for cancer. Interestingly, patients with obesity tend to have an increased tumor burden and decreased T-cell function. It remains unclear how obesity compromises T-cell mediated immunity. To address this question, we modeled the adipocyte niche using the secretome released from adipocytes as well as the niche of stromal cells and investigated how these factors modulated T-cell function. We found that the secretomes altered antigen-specific T-cell receptor (TCR) triggering and activation. RNA-sequencing analysis identified thousands of gene targets modulated by the secretome including those associated with cytoskeletal regulation and actin polymerization. We next used molecular force probes to show that T-cells exposed to the adipocyte niche display dampened force transmission to the TCR-antigen complex and conversely, stromal cell secreted factors lead to significantly enhanced TCR forces. These results were then validated in diet-induced obese mice. Importantly, secretome-mediated TCR force modulation mirrored the changes in T-cell functional responses in human T-cells using the FDA-approved immunotherapy, blinatumomab. Thus, this work shows that the adipocyte niche contributes to T-cell dysfunction through cytoskeletal modulation and reduces TCR triggering by dampening TCR forces consistent with the mechanosensor model of T-cell activation.

bioengineering↗

bioRxiv2022

Multicolor Light-Induced Immune Activation via Polymer Photocaged Cytokines

Cytokines act as potent, extracellular signals of the human immune system and can elicit striking treatment responses in patients with autoimmune disease, tissue damage, and cancer. Yet despite their therapeutic potential, recombinant cytokine-mediated immune responses remain difficult to control as their administration is often systemic whereas their intended sites of action are localized. To address the challenge of spatially and temporally constraining cytokine signals, we recently devised a strategy whereby recombinant cytokines are reversibly inactivated via chemical modification with photo-labile polymers that respond to visible LED light. Extending this approach to enable both in vivo and multicolor immune activation, here we describe a strategy whereby cytokines appended with heptamethine cyanine-polyethylene glycol are selectively re-activated ex vivo using tissue-penetrating near-infrared (NIR) light. We show that NIR LED light illumination of caged, pro-inflammatory cytokines restores cognate receptor signaling and potentiates the activity of T cell-engager cancer immunotherapies ex vivo. Using combinations of visible- and NIR-responsive cytokines, we further demonstrate multi-wavelength optical control of T cell cytolysis ex vivo, as well as the ability to perform Boolean logic using multicolored light and orthogonally photocaged cytokine pairs as inputs, and T cell activity as outputs. Together, this work demonstrates a novel approach to control extracellular immune cell signals using light, a strategy that in the future may improve our understanding of and ability to treat cancer and other diseases.

bioengineering↗

bioRxiv2020

In situ humoral selection in human lupus tubulointerstitial inflammation

ABSTRACTIn human lupus nephritis, tubulointerstitial inflammation (TII) is associated with in situ expansion of B cells expressing anti-vimentin antibodies (AVAs). The mechanism by which AVAs are selected is unclear. Herein, we demonstrate that AVA somatic hypermutation and selection increase affinity for vimentin. However, enzyme-linked immunosorbent assays (ELISAs) suggested that affinity maturation might be a non-specific consequence of increasing polyreactivity. Subsequent multi-color confocal microscopy studies indicated that while TII AVAs often appeared polyreactive by ELISA, they bound selectively to vimentin fibrils in whole cells or inflamed renal tissue. Using a novel machine learning pipeline (CytoSkaler) to quantify the cellular distribution of antibody staining, we demonstrated that TII AVAs were selected for both enhanced binding and specificity in situ. These data suggest a new approach to assess and define antibody polyreactivity based on quantifying the distribution of binding to native and contextually relevant antigens.Competing Interest StatementThe authors have declared no competing interest.View Full Text

immunology↗

bioRxiv2020

Rapid Assembly and Screening of Multivalent Immune Cell-Redirecting Therapies for Leukemia

Therapies that bind with immune cells and redirect their cytotoxic activity towards diseased cells represent a promising and versatile approach to immunotherapy with applications in cancer, lupus, and other diseases; traditional methods for discovering these therapies, however, are often time-intensive and lack the throughput of related target-based discovery approaches. Inspired by the observation that the cytokine, IL-12, can enhance antileukemic activity of the clinically approved T cell redirecting therapy, blinatumomab, here we describe the structure and assembly of a chimeric immune cell-redirecting agent which redirects the lytic activity of primary human T cells towards leukemic B cells and simultaneously co-targets the delivery of T cell-stimulating IL-12. We further describe a novel method for the parallel assembly of compositionally diverse libraries of these bi-specific T cell engaging cytokines (BiTEokines) and their high-throughput phenotypic screening, requiring just days for hit identification and the analysis of structure-function relationships. Using this approach, we identified CD19 x CD3 x IL12 compounds that exhibit ex vivo lytic activity comparable to current FDA-approved therapies for leukemia and correlated drug treatment with specific cell-cell contact, cytokine delivery, and leukemia cell lysis. Given the modular nature of these multivalent compounds and their rapid assembly/screening, we anticipate facile extension of this therapeutic approach to a wide range of immune cells, diseased cells, and soluble protein combinations in the future.

bioengineering↗