Biology subjects

Lai, T. H.

Publications and source records attributed to Lai, T. H..

3 recordsLinked to original sources

bioRxiv2026

Disrupting Myeloid Persistence and Replenishment Enables Sustained Control of Esophageal Squamous Cell Carcinoma

Responses to macrophage-directed therapy can be transient because tumors preserve myeloid support through complementary persistence and replenishment. In esophageal squamous cell carcinoma (ESCC), CSF1R inhibition reduced established tumor-associated macrophages but was followed by expansion of Ly6C/CCR2-positive monocytic and Ly6G-positive granulocytic populations. Low-dose decitabine preferentially restricted recruited populations while sparing a LYVE1-associated macrophage state, exposing reciprocal pharmacologic blind spots. Combined treatment suppressed both arms and produced sustained control across patient-derived organoid xenograft, orthotopic, and immunocompetent models. Neutrophil depletion reproduced initial regression but not sustained control, indicating that the recruited escape arm extended beyond Ly6G-positive granulocytes. Single-cell profiling mapped these vulnerabilities onto a treatment-resolved myeloid architecture comprising a C1qa-positive TAM continuum, a C1qa-negative Ccr2/Ly6c2-high inflammatory monocytic-like compartment, and a LYVE1/MRC1-positive tissue-supportive macrophage state. Human ESCC contained corresponding macrophage programs and an adverse-outcome-associated LYVE1-rich niche. These findings identify state-aware coverage of complementary myeloid vulnerabilities as a strategy to overcome escape from macrophage-directed therapy.

cancer biology↗

bioRxiv2021

A small fraction of progenitors differentiate into mature adipocytes due to constraints on the cell structure change

Differentiating 3T3-L1 pre-adipocytes are a mixture of non-identical culture cells. It is vital to identify the cell types that respond to the induction stimulus to understand the pre-adipocyte potential and the mature adipocyte behavior. To test this hypothesis, we deconvoluted the gene expression profiles of the cell culture of MDI-induced 3T3-L1 cells. Then we estimated the fractions of the sub-populations and their changes in time. We characterized the sub-populations based on their specific expression profiles. Initial cell cultures comprised three distinct phenotypes. A small fraction of the starting cells responded to the induction and developed into mature adipocytes. Unresponsive cells were probably under structural constraints or were committed to differentiating into alternative phenotypes. Using the same population gene markers, similar proportions were found in induced human primary adipocyte cell cultures. The three sub-populations had diverse responses to treatment with various drugs and compounds. Only the response of the maturating sub-population resembled that estimated from the profiles of the mixture. We then showed that even at a low division rate, a small fraction of cells could increase its share in a dynamic two-populations model. Finally, we used a cell cycle expression index to validate that model. To sum, pre-adipocytes are a mixture of different cells of which a limited fraction become mature adipocytes.

bioinformatics↗

bioRxiv2021

Hierarchical Regulation of Autophagy During Adipocyte Differentiation

We previously showed that some adipogenic transcription factors such as CEBPB and PPARG directly and indirectly regulate autophagy gene expression in adipogenesis. The order and the effect of these events are undetermined. In this study, we modeled the gene expression, DNA-binding of transcriptional regulators, and histone modifications during adipocyte differentiation and evaluated the effect of the regulators on gene expression in terms of direction and magnitude. Then, we identified the overlap of the transcription factors and co-factors binding sites and targets. Finally, we built a chromatin states model based on the histone marks and studied their relation with the factors binding. Adipogenic factors differentially regulated autophagy genes as part of the differentiation program. Co-regulators associated with specific transcription factors and preceded them to the regulatory regions. Transcription factors differed in the binding time and location, and their effect on expression was either localized or long-lasting. Adipogenic factors disproportionately targeted genes coding for autophagy-specific transcription factors. To sum, a hierarchical arrangement between adipogenic transcription factors and co-factors drives the regulation of autophagy during adipocyte differentiation.

systems biology↗